New benzazepine derivatives, drugs containing these and use of the same for producing drugs

ABSTRACT

New derivatives of benzazepine, particularly of benzofuro[3 a, 3,2,ef][2]benzazepin of the general formula (I)  
                 
 
     and new compounds of the general formula (III)  
                 
 
     Drugs, containing compounds of formulas (I) and/or (III), which can be used successfully for the treatment of Alzheimer&#39;s disease and related dementia conditions, as well as for the treatment of Langdon-Down syndrome, are also described.

[0001] The invention relates to new compounds and drugs containing thenew compounds as active, pharmaceutical ingredients.

[0002] Likewise, the invention relates to the use of the new compoundsfor the preparation of drugs for the treatment of Alzheimer's diseaseand related dementia conditions, as well as for the treatment ofLangdon-Down Syndrome (mongolism, trisomy 21).

[0003] The acid addition salt of galanthamine, which has the chemicalstructure

[0004] as well as some of its analog, are known as active pharmaceuticalingredients having an inhibitory effect on the synaptic enzyme,acetylcholine esterase. Galanthamine is therefore used pharmacologicallyfor paralysis symptoms resulting from polio mellitus and for differentdiseases of the nervous system.

[0005] Galanthamine and some of its derivatives are also used for thesymptomatic treatment of Alzheimer's disease and related dementiaconditions (EP 236 684 B1).

[0006] Chemically, galanthamine is an alkaloid of the morphine group,which can be obtained from snowdrops (Galanthus woronowii, G. nivalisetc.) and other Amaryllidaceae.

[0007] Aside from obtaining galanthamine from plant sources, chemicalmethods of synthesizing galanthamine and its analogs, including its acidaddition salts, have also become known (WO 95/27715).

[0008] The Down syndrome is attributed to a tripling of chromosome 21,that is, the patients have a set of 47 chromosomes instead of 46. Thiscan be demonstrated relatively simply cytologically. Trisomy 21 isassociated with moderate to severe mental impairment and a series ofsymptoms of physical dysmorphism. A causative treatment is not possibleat the present time. The existing impairment can be influenced byselective therapeutic measures. However, a distress usually remains.

[0009] The new inventive compounds are new benzazepine derivatives,particularly derivatives of benzofuro[3a, 3, 2,ef][2] benzazepine.

[0010] They are compounds of the general formula (I)

[0011] in which

[0012] R₁, R₂ either are the same or different and represent

[0013] hydrogen, F, Cl, Br, I, CN, NC, OH, SH, NO₂, SO₃H, NH₂, CF₃ or

[0014] a lower (C₁-C₆), optionally branched, optionally substituted (Ar)alkyl or (Ar) alkoxy group or

[0015] an amino group, which is substituted by one or two or differentlower (C₁-C₆), optionally branched, optionally substituted (Ar) alkyl or(Ar) alkyl carbonyl or (Ar) alkoxy carbonyl or

[0016] a COOH, COO(Ar) alkyl, CONH, CON(Ar) alkyl group or

[0017] represents —(CH₂)_(n)—Cl, —(CH₂)_(n)—Br, —(CH₂)_(n)—OH,—(CH₂)_(n)—COOH, —(CH₂)_(n)—CN, —(CH₂)_(n)—NC, in which

[0018] it is also possible to define R₁-R₂ jointly as —CH═CH—CH═CH—,—O—(CH₂)_(n)—O—, with n=1 to 3.

[0019] R₃═R₁, particularly OH and OCH₃ and furthermore

[0020] R₂-R₃ can jointly form: —O—(CH₂)_(n)—O—, with n=1 to 3

[0021] R₄, R₅: either are both hydrogen or, alternatively, anycombination of hydrogen or an (Ar) alkyl, (Ar) alkenyl, (Ar) alkinylwith

[0022] S—R₈, wherein R₈ is hydrogen or a lower (C₁-C₁₀), optionallybranched, optionally substituted (Ar) alkyl group

[0023] SO—R₈, SO₂R₈

[0024] OH, O-protective group (such as TMS, TBDMS)

[0025] O—CS—N—R₈ (thiourethanes)

[0026] O—CO—N—R₉, wherein R₉ has the following meaning:

[0027] O—CO—R₅ (ester, R₈ see above), in particular, also esters withthe substitution pattern of amino acids such as

[0028] Furthermore: R₄, R₅=jointly hydrazone (═N—NH—R₁₀, ═N—N(R₁₀, R₁₁),Oximines (═N—O—R₁₁), wherein R₁₀ is hydrogen, a lower (C₁-C₆),optionally branched, optionally substituted (Ar)-alkyl or (Ar)-alkylcarbonyl or (Ar)-alkyl carbonyloxy group as well as a sulfonic acidgroup, such as a tosyl and mesyl group and R₁₁ is hydrogen, a lower(C₁-C₆), optionally branched, optionally substituted (Ar)-alkyl or(Ar)-alkyl carbonyl group, as well as a sulfonic acid group, such as atosyl and mesyl group.

[0029] as well as substituents of the type

[0030] Y₁, Y₂═O, S, NH or N—R₁₀ (excess valences in each case are —H)

[0031] wherein, in the event that R₄═H, R₅ can also be OH and, in theevent that R₅═H, R₄ can also be OH.

[0032] G₁, G₂: jointly or separately have the meaning:

[0033] —C(R₁₃, R₁₄)—, wherein R₁₃, R₁₄ can be hydrogen, OH, a lower,optionally branched, optionally substituted (Ar)-alkyl, aryl,(Ar)-alkoxy or aryloxy group or jointly an alkyl spiro group (C₃ to C₇spiro ring).

[0034] Furthermore, G₁ and G₂ jointly represent

[0035] with m=1 to 7

[0036] G₃: represents CH₂ or ═CO

[0037] R₆ represents a group -(G₄)_(p)-(G₅)_(q)-G₆ with p, q=0 to 1, inwhich G₄ satisfies the following definition

[0038] —(CH₂)_(r)—, —C(R₁₅,R₁₆)(CH₂)—, with R=1 to 6 and R₁₅,R₁₆=hydrogen, lower, optionally branched or optionally substituted(Ar)-alkyl, cycloalkyl, aryl groups

[0039] —O— or —NR₁₅

[0040] with s=1 to 4, t=0 to 4

[0041] that is an ortho, meta or para disubstituted aromatic

[0042] wherein G₇=NR₁₅, O or S,

[0043] G5 can be identical with or different from G₄ and, in the eventthat P=1, additionally represents —S—,

[0044] G₆ fulfills the following definition:

[0045] with

[0046] R₁₇, R₁₈, R₁₉ and R₂₀ individually or jointly are the same ordifferent, hydrogen, lower, optionally branched, optionally substituted(Ar)-alkyl, cycloalkyl or aryl groups, wherein R₁₇ and R₁₈ and R₁₉ andR₂₀ can jointly form a cycloalkyl group (with a ring size of 3-8)

[0047] G₈=O, S, NH, NR₂₁—(CH₂)_(n)—,

[0048] R₂₁═CHO, COOR₁₇ or a heteroaryl group, which is unsubstituted orsubstituted identically or differently by one or several F, Cl, Br, I,NO₂, NH₂, OH, alkyl, alkyloxy, CN, NC or CF₃, CHO, COOH, COOalkyl, SO₃H,SH or S-alkyl groups, (heteroaryl being, in particular, 2-pyridyl,4-pyridyl, 2-pyrimidinyl) or,

[0049] a methyl group, which is substituted by 1-3 phenyl groups, whichare unsubstituted or substituted identically or differently by one ormore F, Cl, Br, I, NO₂, NH₂, alkyl, alkyloxy, CN, NC or CF₃ groups,

[0050] Furthermore, G₆ can be:

[0051] a lower, optionally branched, optionally substituted (Ar)-alkyl,(Ar)-alkenyl, (Ar)-alkinyl, cycloalkyl or aryl groups,

[0052] —O—R₁₇, —NR₁₇R₁₈, phthalamido, —CN or —NC.

[0053] R₇ is identical with R₆ or represents —O—⁽⁻⁾ (N-oxide) or a freeelectron pair (e-pair), wherein R₆ and R₇ can also form a common ring, 3to 8 carbon atoms in size and

[0054] [X] exists only if, and represents an ion of a pharmacologicallyusable inorganic or organic acid, when R₅ and R₆ are present and thenitrogen atoms thus carries a positive charge.

[0055] Z═N or N⁺ in the event that R₆ and R₇ are present jointly and R₇is not O⁻.

[0056] A special case of the new compounds of the general formula (I)are the compounds of the general formula (II)

[0057] wherein the groups have the meanings described for formula (I).This formula arises formally out of formula (I), in that the bond fromC₁ to the furan oxygen is broken and, instead, a bond between C₁ and Zis formed directly.

[0058] Furthermore, the invention comprises the new, substituted,bridged bases of the general formula (III) and their synthesis, andparticularly to 2,5-diazabicyclo[2.2.1]heptane:

[0059] wherein R₂₂

[0060] is a (hetero) aryl group, which is unsubstituted or substitutedidentically or differently by one or several F, Cl, Br, I, NO₂, NH₂, OH,alkyl, alkoxy, CN, NC or CF₃, CHO, COOH, COOalkyl, SO₃H, SH or S-alkylgroups or

[0061] a methyl group, which is substituted by two phenyl groups, whichare substituted identically or differently by one or more F, Cl, Br, I,NO₂, NH₂, OH, alkyl, alkoxy, CN, NC or CF₃, CHO, COOH, COOalkyl, SO₃H,SH or S-alkyl groups,

[0062] R₁₇, R₁₈, n, s having tie meanings given for the general formula(I) and

[0063] R₂₃ -(G₅)_(q)-(G₄)_(p)-G₉

[0064] wherein G₄ and G₅ have the meanings given for the general formula(I) and G₉ is defined as:

[0065] Hydrogen, F, Cl, Br, I, OH, O-ts, 0-ms, O-triflate, COOH, COClCHO, —O—R₁₇, —NR₁₇R₁₈, phthalimido, —CN or —NC or by other groupssuitable for nucleophilic substitutions, addition reactions,condensation reactions, etc.

[0066] Examples of these types of compounds are:

[0067] These compounds of the general formula (III) represent not only apharmaceutically interesting class of compounds, but also find use assubstitutents in a plurality of basic compounds. The compound 105 to 109represent the compounds.

[0068] The inventive drugs can be used successfully for the treatment ofAlzheimer's disease and related dementia conditions, as well as for thetreatment of Langdon-Downs syndrome.

[0069] The invention likewise relates to the use of the compounds usedabove for the preparation of drugs for the treatment of Alzheimer'sdisease and related dementias, as well as for the treatment ofLangdon-Downs syndrome.

[0070] Particularly preferred pursuant to the invention are thecompounds named in the survey below. In the survey, the ACHE inhibitionvalues (IC⁵⁰, that is, the 50% inhibition concentration) of theinventive compounds, which are one of the factors, which determine theeffectiveness, are also given.

[0071] The inhibition of acetylcholine esterase was determined by amodified method of Ellmann (reference 44), human serum from a pool of 10test subjects being used as serum.

[0072] Method: 520 μL of solution of the test substance (concentrationsof 10⁻⁴ to 10⁻⁷ and, in exceptional cases, up to 10⁻⁹ moles/liter wereused) in 0.02 M tris(hydroxymethyl)aminomethane solution, buffered withHCl to a pH of 7.8 and 400 μL of m-nitrophenol solution (SigmaDiagnostics, Art. 420-2) were incubated in the semi-micro cuvette at 37°C. with 40 μL of cholinesterase solution (Sigma Diagnostics, Art.420-MC, diluted 1:15 with water) and 160 μL of serum and the change inthe absorption was measured over 5 minutes against a comparison samplein a Beckmann DU-50 spectrophotometer with a kinetics program. Thevalues were given as a percentage of the comparison sample and theinhibiting concentration (IC⁵⁰) was calculated from the course of thecurve.

[0073] Survey of the New Compounds of the Type of the General Formula:

[X] Subst. Nr. Chir. R₁ R₂ R₃ R₄ R₅ R₆ R₇ Z [X] G₃ IC₅₀ in μMol Gal (−)H H CH₃ OH H CH₃ H N⁻ Br⁻ CH₂ 6 *HBr (+) 1 (+/−) Br H CH₃ OH H CH₃ — N —CH₂ 10 2 (+/−) Br H CH₃ H OH CH₃ — N — CH₂ 3 (−) Br H CH₃ OH H CH₃ — N —CH₂ 4 4 (+/−) Br H CH₃ OH H H — N — CH₂ 5 5 (−) Br H CH₃ OH H H — N —CH₂ 3 6 (+) Br H CH₃ OH H H — N — CH₂ >150 7 (+/−) br H CH₃ H OH H — N —CH₂ 8 (+/−) Br H CH₃ —O—CH₂—CH(CH₃)—O— CHO — N — CH₂ 9 (+/−) H H CH₃—O—CH₂—CH(CH₃)—O— CH₃ — N — CH₂ 10 (+/−) Br H CH₃ —O—CH₂—CH₂—O— CHO — N— CH₂ 11 (+/−) H H CH₃ —O—CH₂—CH₂—O— CH₃ — N — CH₂ 12 (+/−) H H CH₃—O—CH₂—CH₂—O— H CH₃ — N — CH₂ 13 (+/−) Br H CH₃ —O—CH₂—CH₂—O— — N — CH₂14 (+/−) Br H CH₃ —O—CH₂—CH₂—O— CH₂—Ph — N CH₂ 15 (+/−) Br H CH₃ ═O H —N — CH₂ 16 (+/−) Br H CH₃ ═O CH₃ — N — CH₂ 52 17 (−) H H CH₃

H CH₃ — N — CH₂ 70 18 (+) H H CH₃

H CH₃ — N — CH₂ 85 19 (−) H H CH₃

H CH₃ — N — CH₂ 75 20 (+) H H CH₃

H CH₃ — N — CH₂ 120 21 (−) H H CH₃

CH₃ — N — CH₂ 55 22 (+) H H CH₃

CH₃ — N — CH₂ 35 23 (−) H H CH₃

CH₃ — N — CH₂ 25 24 (+) H H CH₃

CH₃ — N — CH₂ 85 25 (−) H H CH₃ H

CH₃ — N — CH₂ 45 26 (−) H H CH₃ H

CH₃ — N — CH₂ 27 (+) H H CH₃ H

CH₃ — N — CH₂ 28 (−) H H CH₃ H

CH₃ — N — CH₂ 29 (−) H H CH₃ H

CH₃ — N — CH₂ >150 30 (+) H H CH₃ H

CH₃ — N — CH₂ 120 31 (−) H H CH₃ H

CH₃ — N — CH₂ >>150 32 (−) H H CH₃ H

CH₃ 100 33 (+/−) Br H CH₃

H CH₃ — N — CH₂ 34 (+/−) Br H CH₃

H CH₃ — N — CH₂ 35 (+/−) Br H CH₃ OH H n-Pentyl — N — CH₂ 36 (+/−) Br HCH₃ O-TBDMS H H — N — CH₂ 37 (+/−) Br H CH₃ O-TMS H CH₃ — N — CH₂ 38(+/−) Br H CH₃ O-TBDMS H CH₃ — N — CH₂ 39 (+/−) H H CH₃ O-TBDMS H CH₃ —N — CH₂ 40 (+/−) Br H CH₃ Ethlenglykolketyl CH₂—Ph — N — CH₂ 41 (+/−) BrH CH₃ ═O Allyl — N — CH₂ 42 (+/−) Br H CH₃ OH H Allyl — N — CH₂ 43 (+/−)H H CH₃ OH H allyl — N — CH₂ 44 (+/−) Br H CH₃ ═O CH₂—Ph — N — CH₂ 45(+/−) Br H CH₃ OH H CH₂—Ph — N — CH₂ 46 (+/−) H H CH₃ OH H CH₂—Ph — N —CH₂ 47 (+/−) H H CH₃ ═O CH₂—Ph — N — CH₂ 48 (+/−) Br H CH₃ O—COCH₃ HCOCH₃ — N — CH₂ 49 (+/−) Br H CH₃ OH H n-Hexyl — N — CH₂ insol. 50 (+/−)Br H CH₃ OH H Propargyl — N — CH₂ insol. 51 (+/−) Br H CH₃ OH H CH₂COOEt— N — CH₂ 20 52 (+/−) Br H CH₃ OH H CH₂CN — N — CH₂ insol. 53 (+/−) Br HCH₃ OH H CH₂CONH₂ — N — CH₂ 54 (+/−) Br H CH₃ OH H

— N — CH₂ 3 55 (+/−) Br H CH₃ OH H

— N — CH₂ 56 (+/−) Br H CH₃ OH H

— N — CH₂ 57 (+/−) Br H CH₃ OH H

— N — CH₂ 58 (+/−) Br H CH₃ OH H

— N — CH₂ 0, 2 59 (+/−) Br H CH₃ OH H CO—CH₃ — N — CH₂ 60 (+/−) Br H CH₃OH H CO—COOEt — N — CH₂ 61 (+/−) Br H CH₃ OH H CO—(CH₂)₂—COOCH₃ — N —CH₂ insol. 62 (+/−) Br H CH₃ OH H COOCH₃ — N — CH₂ insol. 63 (+/−) Br HCH₃ OH H t-BOC — N — CH₂ 64 (+/−) Br H CH₃ OH H CO—C₁₅H₃₁ — N — CH₂ 65(+/−) Br H CH₃ OH H Ethyl — N — CH₂ 66 (+/−) Br H CH₃ OH H CO—(CH₂)₂COOH— N — CH₂ >150 67 (+/−) Br H CH₃ OH H CO—COOH — N — CH₂ 68 (+/−) Br HCH₃ OH H CH₂—CH₂—OH — N — CH₂ 69 (+/−) H H CH₃ OH H CH₂—CH₂—OH — N — CH₂70 (+/−) Br H CH₃ OH H CH₂—CH₂—OH — N — CH₂ 71 (+/−) Br H CH₃ OH HCH₂—COOH — N — CH₂ 72 (+/−) H H CH₃ OH H CO—C₁₅H₃₁ — N — CH₂ 73 (+/−) HH CH₃ OH H CH₂CN — N — CH₂ 74 (+/−) H H CH₃ OH H

— N — CH₂ 75 (+/−) H H CH₃ ═N—OTs CH₃ — N — CH₂ 76 (+) H H CH₃ ═N—OH CH₃— N — CH₂ insol. 77 (−) H H CH₃ ═N—OH CH₃ — N — CH₂ insol. 78 (+) H HCH₃ ═N—OCH₃ CH₃ — N — CH₂ insol. 79 (−) H H CH₃ ═N—OCH₃ CH₃ — N —CH₂ >150 80 (+/−) H H CH₃ ═NH CH₃ — N — CH₂ 81 (−) H H CH₃ ═N—NH—CH₃ CH₃— N — CH₂ >150 82 (+/−) H H CH₃ ═N—N(CH₃)₂ CH₃ — N — CH₂ insol. 83 (+/−)H H CH₃ ═N—HN—(CH₂)₂OH CH₃ — N — CH₂ >150 84 (+/−) H H CH₃ ═N—NH—CHO CH₃— N — CH₂ >150 85 (+/−) H H CH₃ ═N—NH-tBOC CH₃ — N — CH₂ >150 86 (+/−) HH CH₃ ═N—NH-pTs CH₃ — N — CH₂ 87 (+/−) H H CH₃

CH₃ — N — CH₂ insol. 88 (+/−) H H CH₃

CH₃ — N — CH₂ >150 89 (+/−) H H CH₃

CH₃ — N — CH₂ >150 90 (+/−) H H CH₃ ═N—NH₂ CH₃ — N — CH₂ 40 91 (−) H HCH₃ OH H

CH₃ N⁻ BR⁻ CH₂ 8 92 (−) H H CH₃ OH H

CH₃ N⁻ Cl⁻ CH₂ 2 93 (−) H H CH₃ OH H

CH₃ N⁺ Cl⁻ CH₂ 5 94 (−) H H CH₃ OH H

CH₃ N⁺ BR⁻ CH₂ 4 95 (−) H H CH₃ OH H

CH₃ N⁺ Cl⁻ CH₂ 6 96 (+) H H CH₃ OH H

CH₃ N⁺ Cl⁻ CH₂ 97 (+) H H CH₃ OH H

CH₃ N⁺ Cl⁻ CH₂ 98 (−) H H CH₃ OH H —O^(−CH) ₃ N⁺ — CH₂ insol. 99 (−) H HCH₃ OH H Propargyl CH₃ N⁺ BR⁻ CH₂ 100 (−) H H CH₃ OH H CH₂—CONH₂ CH₃ N⁺Hal⁻ CH₂ 101 (+/−) Br H CH₃ ═O CH₃ — N — C═O 102 (+/−) Br H CH₃ OH H CH₃— N — C═O 103 (+/−) Br H CH₃ O-TBDMS H CH₃ — N — C═O 104 (−) H H CH₃ OHH CH₃ — N — CH₂ 105 (+/−) Br H CH₃ OH H

— N — CH₂ 106 (+/−) H H CH₃ OH H

— N — CH₂ 107 (+/−) Br H CH₃ OH H

— N — CH₂ 108 (+/−) Br H CH₃ OH H

— N — CH₂ 109 (+/−) Br H CH₃ OH H

— N — 110 (+/−) Br H CH₃ —O—CH₂CH₂—O— CH₃ — N — CH₂ 111 (+) Br H CH₃ OHH CH₃ — N — CH₂ >150 112 (+/−) H H CH₃ OH H H — N — CH₂ 7 117 (−) NO₂ HCH₃ OH H CH₃ — N — CH₂ 118 (−) NH₂ H CH₃ OH H CH₃ — N — CH₂

[0074] The general formula (II) is a special case of the general formula(I)

formula (II) PAT II Nr. Chiral R₁ R₂ R₃ R₄ R₅ G₃ DB* IC₅₀ 113 (+/−) Br HCH₃ ═O CH₂ yes 5 114 (+/−) Br H CH₃ OH H CH₂ yes 115 (+/−) H H CH₃ OH HCH₂ yes >150 116 (+/−) Br H CH₃ OH H CH₂ no 50 DB = double bond Pleasenote: “Chiral” refers in the whole of the Table to the plurality of therespective educt. The values of the rotation of the products aredetermined in the experimental part.

[0075] The compounds, contained in drugs pursuant to the invention, canbe administered in any suitable chemical or physical form, such as anacid addition salt. For example, they can be administered ashydrobromide, hydrochloride, methyl sulfate or methyl iodide.

[0076] The inventive drugs can be administered to patients orally or bysubcutaneous or intravenous injection or intracerebroventricularly bymeans of an implanted container.

[0077] It may be necessary to start with doses lower than effectiveones.

[0078] Typical dosing rates when administering drugs containing theactive ingredients proposed pursuant to the invention depend on thenature of the compound used and on the condition of the patient.Typically, dosage rates lie in the range of 0.01 to 1.0 mg per day perkg of body weight, depending on the age, the mental condition and othermedication of the patient.

[0079] The inventive drugs may be present in the following specificformulations:

[0080] tablets or capsules containing 0.5 to 50 mg

[0081] parenteral solution containing 0.1 to 30 mg/mL

[0082] liquid formulation for oral administration in a concentration of0.1 to 15 mg/mL.

[0083] The inventive compounds can also be a transdermal system, inwhich 0.1 to 10 mg are released per day.

[0084] A transdermal dosing system consists of a reservoir layer, whichcontains 0.1-30 mg of the active substance as free base or salts, ifnecessary, together with a penetration accelerator, such as dimethylsulfoxide, or a carboxylic acid, such as octanoic acid, and askin-neutral polyacrylate, such as hexyl acrylate/vinyl acetate/acrylicacid copolymer together with a plasticizer, such as isopropyl myristate.The covering is an outer layer, which is impermeable to the activeingredient, such as metal-coated, siliconized polyethylene Band-Aid witha thickness of, for example, 0.35 mm. A dimethylaminomethylacrylate/methyl acrylate copolymer in an organic solvent, for example,is used to produce an adhesive layer.

[0085] Some examples of methods, by means of which inventive compoundscan be synthesized, are given below.

EXPERIMENTAL SECTION

[0086] General Instructions

[0087] Thin-layer chromatography with silica gel 60 F₂₅₄ (Merck, Art.No. 5554).

[0088] Abbreviations used:

[0089] NH₄OH concentrated aqueous ammonia

[0090] PE petroleum ether or naptha (40°-60° C.)

[0091] p-Ts=p-Tos=p-toluene sulfamide

[0092] CE=capillary electrophoresis

[0093] Rotations are generally recorded at a concentration of C=0.1.

[0094] The melting points are determined by the Kofler method using amicroscope with a hot stage; the values are not corrected.

[0095] The glass autoclave comes from Büchi (TinyClave, MiniClave).

[0096] The water content of the solvent where given is determined by theKarl Fischer method.

[0097] The element microanalysis were carried out in the MicroanalyticalLaboratory at the Institute for Physical Chemistry of the University ofVienna under the direction of Mag. J. Theiner.

[0098] NMR spectra were recorded on a Büchi 200 FS FT-NMR spectrometer,CDCl₃ or DMSO-d₆ being used as solvent.

[0099]¹H-NMR: measurement frequency 200.13 MHz, internal standard: CDCl₃(δ=7.26 ppm)

[0100] or

[0101] DMSO-d₆ (δ=2.50 ppm)

[0102]¹³C-NMR: measurement frequency 50.32 MHz, internal standard: CDCl₃(δ=77.0 ppm)

[0103] or

[0104] DMSO-d₆ (δ=39.5 ppm)

[0105] The splittings in the NMR spectroscopy are labeled as follows:

[0106] s=singlet d=doublet t=triplet

[0107] q=quartet m=multiplet

[0108] Where necessary, the multiplicities of the ¹³C spectra weredetermined by DEPT experiments, the assignments of the ¹H spectraoptionally by COSY experiments. Uncertain assignments were marked withan asterisk.

[0109] Experimental Section

[0110] (±) 8-Bromogalanthamine (1), (±) 8-Bromo-epigalanthamine (2)

[0111] To a suspension of 4.0 g (10.5 mmoles) of bromo-N-formylnarwedine in 60 mL of toluene, 24 mL (36 mmoles) of 1M DIBAL-H solutionin toluene is added dropwise at 0° C. The reaction is stirred for onehour at room temperature, the remaining reducing agent is decomposedwith water and 20 mL of ammonia are subsequently added. After stirringfor 20 minutes at room temperature, the precipitated material isfiltered off, the organic phase is separated and the aqueous phasewashed with 50 mL of toluene. The combined organic phases are dried oversodium sulfate, filtered and the solvent is removed under vacuum. Theresidue is separated by means of column chromatography. Yield: 0.9 g(23.3%) of one and 0.8 g (20.7%) of two.

[0112] Bromogalanthamine (1) data:

[0113] molecular weight C₁₇H₁₉BrNO₃: 365.23

[0114] IR(KBr): 689,03 m; 778,57 m; 839,37 m; 989,86 m; 1050,66 s;1212,43 s; 1279,87 s; 1434,08 s; 14,72 s; 16113,99 s; 2667,39 m;3370-3778 br.

[0115]¹H-NMR (CDCl₃): 6,9 (s, 1 H); 6.06 (m, 2 H); 4,60 (d, 1 H); 4,15,(t, 1 H); 3,92 (d, 1 H); 3,82 (s, 3 H); 3,24 (m, 1 H); 2,98 (dt, 1 H);2,68 (dd, 1 H); 2,42 (s, 3 H); 2,05 (m, 2 H); 1,60 (dt, 1 H).

[0116]¹³C-NMR (CDCl₃): 145,32 s; 144,00 s 133,96 s; 127,95 d; 127,68 s;126,51 d; 115,61 d; 114,22 s; 88,56 d; 61,58 d; 58,56 t; 55,95 q; 53,26t; 48,56 s; 42,06 q; 33,47 t; 29,69 t.

[0117] Epi-bromogalanthamine (2) data:

[0118] molecular weight C₁₇H₁₉BrNO₃: 365.23

[0119] IR(KBr): 667,95 w; 752 m; 836,68 m; 1040,31 s; 1208,39 s; 12,82m; 1435,25 m; 1485,72 m; 1512,94 w; 1558,27 w; 1615,19 m; 1667,14 w;2943,24 w; 3360-3575 br.

[0120]¹H-NMR (CDCl₃): 6,85 (s, 1 H); 5,96 (AB, 22); 4,69 (m, 2 H); 4,28(d, 1 H); 3,90 (d, 1 H); 3,83 (s, 1H; 3,25 (m, 1 H); 2,95 (m) 1 H); 2,85(dt, 1 H); 2,36 (s 3 H); 2,15 (td, 1 H), 1,69 (m, 2 H).

[0121]¹³C-NMR (CDCl₃+DMSO-d₆): 145,84 s; 143,49 s; 133,89 s; 133,14 d;126,12 s; 124,35 d; 115,04 s; 113,01 s; 88,26 d; 61,10 d; 57,44 t; 55,58q; 52,84 t; 47,86 s; 41,20 q; 33,35 t; 31,43 t.

[0122] (±) Bromogalanthamine (1)

[0123] Method 1:

[0124] To a solution of 2.0 g (5.6 mmoles) of (4) in 20 mL of water, 5mL of 89% HCOOH and 5 mL of 37% formaldehyde are added and boiled underreflux. After being boiled for 15 minutes, the reaction mixture isdiluted with water, the pH is adjusted with 25% ammonia to a value of 9and the solution is extracted three times with 20 mL of methylenechloride. The combined organic phases arc dried with sodium sulfate,filtered and the solvent is evaporated under vacuum. Chromatographicpurification of the residue (150 mg of silica gel) CHCl₃: MeOH=97:→95:5)results in a colorless foam. Yield: 2.0 g (96.4%)

[0125] Method 2:

[0126] To a suspension of 10 g (26.4 mmoles) of bromo-N-formyl narwedinein 200 mL of THF, 100 mL (100 mmoles) of a 1 M solution of L-selectrideis added dropwise at 0° C. during a period of 30 minutes. After stirringfor 30 minutes at 0° C., the reagent is decomposed with water and thereaction mixture treated with 100 mL of a 25% ammonia solution. After 30minutes of stirring at room temperature, the solvent is concentratedunder vacuum to half its volume, transferred to a separating funnel,treated with 100 mL of 25% ammonia and extracted three times with 200 mLof methylene chloride. The combined organic phases are dried over sodiumsulfate, filtered and the solvent is evaporated under vacuum. To theresidue, 50 mL of water, 30 mL of 98% HCOOH and 30 mL of a 37%formaldehyde solution are added and the reaction mixture is boiled underreflux. After 15 minutes of boiling, the reaction is neutralized withammonia and extracted three times with 200 mL of methylene chloride. Thecombined organic phases are dried over sodium sulfate, filtered and thesolvent is evaporated under vacuum. Chromatographic purification of theresidue (600 mg of silica gel) CHCl₃: MeOH=9:1:→8:2) results in acolorless foam. Yield: 6.4 g (66.2%).

[0127] Method of Synthesizing rac., (−) or (+) Bromogalanthamine (1,3,III):

[0128] Method A:

[0129] To a solution of 4.00 g (10.8 mmoles) of nivaline in 40 mL of 30%fonnic acid, 40 mL of 30% hydrogen peroxide solution are added and thereaction mixture is heated rapidly to 100° C. After 20 minutes, thereaction mixture is cooled rapidly to room temperature, made alkalinewith concentrated aqueous ammonia and extracted three times with 50 mLof ethyl acetate. The organic phase is washed once with saturated,aqueous sodium chloride solution, dried (sodium sulfate), filtered andevaporated, 2.55 g (64% of the theoretical yield) of colorless crystalswith a melting point of 76°-77° C. and a rotation of α_(D)²⁰[CHCl₃]=−93° of 3 being obtained.

[0130] TLC: CHCl₃: MeOH=9:1

[0131] Method B:

[0132] A solution of 1.0 g (2.84 mmoles) of rac.N-demethylbromogalanthamine (4) in 1 mL of 37% of formaldehyde, 2 mL offormic acid and 5 mL of water are stirred for 3 hours at 70° C. Thesolution is allowed to cool, made alkaline with concentrated aqueousammonia and left to crystallize for 20 hours at 4° C. The precipitate isfiltered off, dried at 50° C./20 mm, 0.85 g (82% of the theoreticalyield) of colorless crystals of 1, melting at 76° to 77° C. beingobtained.

[0133] TLC: CHCl₃: MeOH=9:1

[0134] Method C:

[0135] See the general procedure for the reduction with L-selectride.

[0136] NMR data of (1,3, III)

[0137]¹H-NMR (CDCl₃; δ (ppm)): 1.60 (ddd, 1H, H-9, J_((9,9′))=14.2 Hz);1.90-2.15 (m, 2H, H-9′/5, J_((5,5′))=15.1 Hz); 2.20 (b, 1H tauscht D₂O,OH); 2.45 (s, 3H, NCH₃); 2.65 (ddd, 1H, H-5′, J_((5,5′))=15.1 Hz); 2.95(ddd, 1H, H-10, J_((10,10′))=15.6 Hz); 3.25 (ddd, 1H, H-10′,J_((10,10′))=15.6 Hz); 3.80 (s, 3H, OCH₃); 3.95 (d, 1H, H-12,J_((12,12′))=16.0 Hz); 4.15 (dd, 1H, H-6); 4.30 (d, 1H, H-12′,J_((12,12′))=16.0 Hz); 4.60 (b, 1H, H-4a); 5.95-6.10 (m, 2H, H-7/8);6.90 (s, 1H, H-2)

[0138]³C-NMR (CDCl₃; δ (ppm)): 29.7 (t, C-5); 33.5 (t, C-9); 42.1 (q,NCH₃); 48.6 (s, C-8a); 53.3 (t, C-10); 55.9 (q, OCH₃); 58.7 (t, C-12);61.6 (d, C-6); 88.6 (d, C-4a); 114.2 (s, C-1); 115.6 (d, C-8); 126.5 (t,C-2); 127.6 (s, C-12a); 127.9 (t, C-7); 134.0 (s, C-12b); 144.0 (s,C-3a); 145.3 (s, C-3)

[0139] N-Demethylbromogalanthamine (4):

[0140] Method A

[0141] N-formyl bromonarwedine (50.0 g, 132 mmoles) is suspended in 250mL of absolute tetrahydrofuran and treated at −25° to −20° C. with 430mL (430 mmoles) of a 1N solution of L-selectride in tetrahydrofuran.After 3 hours, the reaction mixture is hydrolyzed with a 1:1 solution ofethanol in tetrahydrofuran, concentrated to about 200 mL, treated with400 mL of ethanol and once again concentrated to 200 mL, in order toremove the borate ester. The residue is taken up in 500 mL of ethanol,treated with 62% aqueous hydrobromic acid until a pH of 1 is reached andstirred for 24 hours at room temperature. The resulting precipitate isfiltered off with suction and washed with a little ethanol. After beingdried, the precipitate is dissolved in 500 mL of water. The aqueousphase is slowly made alkaline with concentrated aqueous ammonia whilebeing cooled and stirred well, so that the product precipitates. Theprecipitate is left to crystallize in the refrigerator and then filteredoff with suction. By extraction of the filtrate with ethyl acetate, asecond fraction of the product is obtained, the total yield being 33.5 g(72% of the theoretical yield) of colorless crystals of 4.

[0142] TLC: CHCl₃: MeOH−95:5

[0143] Method B

[0144] See general procedure for reducing with L-selectride.

[0145]¹H-NMR (CDCl₃; δ (ppm)): 1.65-1.85 (m, 2H, H-9/9′), 1.98 (ddd, 1H,H-5); 2.25 (b, 2H tauschen D₂O, NE/OH); 2.62 (ddd, 1H, H-5′); 3.05-3.35(m, 2H, H-10/10′); 3.80 (s, 3H, OCH₃); 3.85 (d, 1H, H-12,J_((12,12′))=14.7 Hz); 4.10 (dd, 1H, H-6); 4.48 (d, 1H, H-12′,J_((12,12′))=14.7 Hz); 4.56 (b, 1H, H-4a); 5.90-6.05 (m, 2H, H-7/8);6.85 (s, 1H, H-2)

[0146]¹³C-NMR (CDCl₃; δ (ppm)): 29.7 (t, C-5); 39.8 (t, C-9); 46.6 (t,C-10); 49.3 (s, C-8a); 52.7 (t, C-12); 56.0 (q, OCH₃); 61.7 (d, C-6);88.4 (d, C-4a); 113.0 (s, C-1); 115.5 (d, C-8); 126.8 (d, C-2); 127.9(d, C-7); 131.6 (s, C-12a); 134.1 (s, C-12b); 144.0 (s, C-3a); 145.8 (s,C-3)

[0147] (±) N-Dimethyl-bromogalanthamine (4), (±)N-Demethyl-epibromo-galanthamine (7)

[0148] To a suspension of 1.0 g (2.6 mmoles) of bromo-N-formyl narwedinein 5 mL of THF, 3.0 g (11.8 mmoles) of LiAlH(t-BuO)₃ in 15 mL of THF isadded dropwise at 0° C. over a period of 30 minutes. After being stirredat 0° C. for 30 minutes, the reaction mixture is refluxed. After 22hours of refluxing, the complex, formed with the reagent, is decomposedwith water and the reaction mixture treated with 10 mL of 25% ammoniasolution. After 30 minutes of stirring at room temperature, 50% of thesolvent is evaporated under vacuum, the remainder is transferred to aseparating funnel, mixed with 10 mL of 25% ammonia solution andextracted three times with 20 mL of methylene chloride. The combinedorganic phases are extracted with sodium sulfate and filtered and thesolvent is evaporated under vacuum. Chromatographic purification of theresidue (60 g of silica gel) CHCl₃: MeOH=95:5→9:1→8:2) results in twoproducts: 300.0 mg (32.2%) of N-demethyl-bromogalanthamine (4) as acolorless foam and 270 mg (29.0%) of N-demethyl-epibromoalanthamine (7)as a colorless foam.

[0149] N-demethyl-epibromogalanthamine (7) data:

[0150] Molecule: C₁₆H₁₈BrNO₃: 352,21

[0151] IR(KBr): 781,60 w; 834,28 w; 976,63 w; 1050,28 m; 1179,73 m;1211,87 m; 1280,07 m; 1435,24 m; 1486,10 m; 1616,37 m; 2923,54 w;3700-2900 mbr.

[0152]¹H-NMR (CDCl₃): 6,86 (s, 1); 5;92 (AB, 2H); 4,56 (m, 2H); 4,50 und3,82 (AB, 2H); 3,80 (s, 3H); 3,28, (m, 2H); 2,52, (m, 1H); 2,20-1,70 (m,3H).

[0153]¹³C-NMR (CDCl₃): 146,73 s; 143,91 s; 134,10 s; 132,17 s; 132,17 d;131,48 d; 126,34 d; 115,34 d; 112,44 s; 88,51 d; 62,81 d; 56,10 q; 52,34t; 49,25 s; 46,82 t; 40,52 t; 32,07 t.

[0154] (−)-N-Demethylbromogalanthamine (5) and(−)-N-Demethylbromogalanthamine (6)

[0155] (−)-N-Demethylbromogalanthamine (5)

[0156] To a solution of 10.0 g (28.4 mmoles) of rac.N-demethylbromogalanthamine (4) in 30 mL of methanol, a solution of 4.4g (11.4 mmoles) of (−)-O,O-di-p-toluoyl tartaric acid in 5 mL ofmethanol is added dropwise and subsequently rinsed with 1 mL of ethanol.The solution is seeded (without seeding, crystal formation can takeseveral weeks) and allow to stand for 2 days at 4° C. After scratchingwith a glass rod, the solution is left standing for a further 2 to 5days at 4° C., scratching with a glass rod being repeated several times.Subsequently, the precipitate itself is filtered off with suction,washed three times with ice cold methanol and taken up in 100 mL ofwater. The aqueous phase is made alkaline with aqueous ammonia andextracted three times with 60 mL of ethyl acetate. The combined organicphases are washed once with saturated aqueous sodium chloride solution,dried (sodium sulfate, activated charcoal), filtered and evaporated,1.90 g (38% of the theoretical yield) of colorless crystals with arotation of α_(D) ²⁰ [CHCl₃]=−104° (after CE: >99.9%) of 5 beingobtained. The methanol mother liquor is evaporated, the residue taken upin 100 mL of water and treated in the same way as the pure salt above,7.13 g (88% of the theoretical yield) of crude product being recovered,which is used for obtaining 6.

[0157] (−)-N-Demethylbromogalanthamine (6)

[0158] To a solution of 7.13 g (20.2 mmoles) of recovered (from 5)N-demethylbromogalanthamine (this slightly concentrated product formscrystals more rapidly than racemic (4)) in 10 mL of methanol, a solutionof 3.12 g (8.1 mmoles) of (+)-O,O-di-p-toluoyl tartaric acid in 4 mL ofmethanol is added dropwise, a further 1 mL of methanol being used forrinsing. The solution is seeded with a crystal (without seeding, crystalformation can take several weeks) and treated as in the recovery of 5,2.02 g (57% of the theoretical yield) of colorless crystals with arotation of α_(D) ²⁰ [CHCl₃]=+102° (after CE: >99.9%) of 6.

[0159] C₁₆H₁₈BrNO₃ * 1.05 C₂₀H₁₈O₈ * 1.01 H₂O (JOS 1500) 776.11 g/mol

[0160] calculated: C57.26 H5.05 N1.80

[0161] found : C57.28 H5.12 N1.82

[0162] (±) Bromo-N-formyl narwedine propylene glycol ketal (8)

[0163] Bromo-N-formyl narwedine (100 g), 100 g of propylene glycol and0.5 g of sulfuric acid in 800 mL of toluene (two phases at roomtemperature) are refluxed with vigorous mechanical stirring (above about90° C., homogeneous) for 14 hours with removal of water. After cooling,the phases were separated (the toluene phase being the upper phase) thepropylene glycol phase was extracted twice with 100 mL of toluene, thecombined toluene phases were shaken twice with 200 mL of saturatedNaHCO₃ solution, dried over sodium sulfate and evaporated: Yield: 115.3g of a yellowish foam (8) (100% of the theoretical yield, crude), whichcrystallized overnight. Column chromatography of 1.0 g (60 g of silicagel 60, CHCl₃/1-2% MeOH) resulted in 0.80 g of a colorless foam, whichcrystallized from ethyl acetate. Melting point: 170°-171° C.

[0164] Molecule C₂₀H₂₂BrNO₅: 436.28

[0165]¹H-NMR (CDCl₃): 8.12 (d, H), 6.88 (s, H), 5.96-6.17 (m, H), 5.75(dd, H), 5.68 (d, H/2), 5.10 (d, H/2), 4.53 (b, H), 4.48 (d, H/2), 4.31(d, H/2),3.12-4.38 (m, 5H), 3.82 (s, 3H), 2.56-2.80 (m, H), 2.05-2.35(dd, H), 1.83-2.05 (m, 2H), 1.22-1.47 (m, 3H).

[0166]¹³C-NMR (CDCl₃): 162.48, 161.72, 147.17, 144.89, 144.64, 132.16,129.04, 128.51, 129.57, 127.82, 127.70, 127.61, 115.70, 115.48, 127.09,126.77, 126.5, 113.20, 111.66, 102.38, 102.22, 87.25, 87.07, 73.38,72.46, 71.67, 71.41, 71.23, 70.55, 70.28, 55.92, 51.52, 46.18, 48.43,40.77, 39.29, 36.07, 35.97, 34.58, 33.68, 33.44, 33.13, 18.68, 17.59,17.45.

[0167] Comment—NMR, diastereoisomers: Because of the additionallyintroduced chiral center by means of the (±) propylene group,diastereoisomers are formed, which cause signal splitting in addition tothat caused by the formyl group.

[0168] (±) Narwedine-propylene Glycol Ketal (9)

[0169] LiAlH₄ (37.5 g) is added under argon into a previously dried, 4 Lmulti-neck flask, into which 800 mL of THF are then run from a droppingfunnel. The temperature rises with vigorous foaming to about 45° C.(depends on the water content of the THF and of the reaction flask).

[0170] A suspension of 114 g of (8) (crude) in THF was added dropwiseover 15 minutes, the temperature increasing to the refluxing temperature(65°-68° C.). Refluxing with mechanical stirring was now continued for10 hours, after which the reaction mixture was cooled. 100 mL of waterin 100 mL of THF were then added dropwise with cooling.

[0171] Removal of 10 mL, making alkaline with ammonia, extraction withethyl acetate (3×20 mL) and evaporation yielded an oily product (9).Column chromatography (5 g of silica gel 60, CHCl₃/3-5% MeOH) of 0.17 gresulted in 0.1 g of colorless foam.

[0172] Molecule: (C₂₀H₂₅NO₄): 343.42

[0173]¹H-NMR (CDCl₃): 6.60 (dd, 2H), 6.16 (dt, H), 5.68 (dd, H)) 4.55(m, H), 4.38-4.00 (m, 3H), 3.80 (s, 3H), 3.68-2.95 (m, 4H), 2.78-2.60(m, H), 2.35 (s, 3H), 2.24-2,02 (m, 2H), 1.62 (bd, H) 1.28 (t, 3H).

[0174]¹³C-NMR (CDCl₃): 146.59, 143.92, 132.04, 131.90, 129.57, 129.16,128.86, 128.76, 128.39, 127.44, 126.92, 126.12, 126.02, 121.16, 111.05,110.90, 110.77, 102.87, 102.73, 87.23, 73.15, 72.24, 71.43, 71.12,70.44, 70.17, 60.28, 55.59, 55.53, 55.45, 53.83, 47.87, 47.80, 47.75,41.80, 41.70, 34.84, 33.95, 33.66, 33.37, 18.66, 17.62, 17.43.

[0175] Comment—NMR, diastereoisomers: Because of the additionallyintroduced chiral center by means of the (±) propylene group,diastereoisomers are formed, which cause signal splitting in addition tothat caused by the formyl group.

[0176] N-formyl Bromonarwedine Ethylene Glycol Ketal (10):

[0177] N-formyl bromonarwedine (10.0 g, 26.5 mmoles) in 20 g of ethyleneglycol and 200 mL of toluene are refluxed with 0.1 mL of concentratedsulfuric acid using a water separator. After 24 hours, the toluene phaseis decanted off and the ethylene glycol phase boiled out once withtoluene. The combined toluene phases are washed twice with saturated,aqueous, sodium hydrogen carbonate solution and evaporated, colorlesscrystals of 10, melting at 192°-193° C. being obtained quantitatively.EtOAc: MeOH=99:1

[0178]¹H-NMR (CDCl₃; δ (ppm)): 1.75-2.10 (m, 2H, H-9/9′); 2.15 (dd, 1H,H-5, J_((5,5′))=16.5 Hz); 2.65 (dd, 1H, H-5′, J_((5,5′))=16.5 Hz); 3.60(ddd, 1H, H-10); 3.80 (s, 3H, OCH₃); 3.90-4.10 (m, 5H, H-10′,O—CH₂—CH₂—O); 4.30 (d, 1H, H-12_(Conformer A), J_((12,12′))=17.8 Hz);4.50 (d, 1H-12_(Conformer B)); 4.55 (b, 1H, H-4a); 5.10 (d, 1H,H-12′_(Conformer A), J_((12,12′))=17.8 Hz); 5.65 (d, 1H,H-12′_(Conformer B)); 5.70 (d, 1H, H-8); 6.10 (t, 1H, H-7); 6.85 (s, 1H,H-2); 8.10, 8.15 (2*s, 1H, CHO_(Conformer A/B))

[0179]¹³C-NMR (CDCl₃; δ (ppm)): 32.9 (t, C-5); 36.0 (t, C-9); 39.3, 40.7(2* t, C-10_(Conformer A/B)); 48.4 (s, C-8a); 46.1, 51.4 (2* t,C-12_(Conformer A/B)); 55.9 (q, OCH₃); 64.2, 65.1 (2* t, O—CH₂—CH₂—O);86.9, 87.1 (2* s, C-4a_(Conformer A/B)); 102.0 (s, C-6); 111.6 (d, C-2);115.4, 115.7 (2* d, C-8_(Conformer A/B)); 126.4 (s, C-12a); 126.7 (s,C-1); 127.5, 127.7 (2* t, C-7_(Conformer A/B)); 132.0, 132.1 (2* s,C-12b_(Conformer A/B)); 144.6, 144.8 (2* s, C-3a_(Conformer A/B)); 147.1(s, C-3); 161.6, 162.4 (2* s, CHO_(Conformer A/B))

[0180] Narwedine ethylene glycol ketal (11):

[0181] Method A:

[0182] To a suspension of 2.0 g (4.74 mmoles) of 10 in 50 mL of absolutetetrahydrofuran, 20 mL of a 0.9 molar lithium aluminum hydride solutionin diethyl ether are added dropwise at 0° C. The reaction mixture issubsequently allowed to warm up to room temperature and finally refluxed(boiling point: 52° C.). After 50 hours, the reaction mixture is cooledand hydrolyzed with 3 mL of a 2:1 mixture of tetrahydrofuran and water.After that, 50 mL of water and 50 mL of concentrated aqueous ammonia areadded and the aqueous is extracted three times with 50 mL of ethylacetate. The combined organic phases are washed once with saturatedsodium chloride solution, dried (sodium sulfate) and evaporated. Bypurification with MPLC using EtOAc:MeOH=8:2, 820 mg (52% of thetheoretical yield) of colorless crystals of 11, melting at 109°-110° C.are obtained.

[0183] TLC: CHCl₃:MeOH=9:1

[0184] Method B:

[0185] (−) Narwedine (1.0 g, 3.5 mmoles) in 2.0 g of ethylene glycol and20 mL of toluene are refluxed with 0.05 mL of concentrated sulfuric acidusing a water separator. After 24 hours, the toluene phase is decantedoff and the ethylene glycol phase boiled out once with toluene. Thecombined toluene phases are washed twice with saturated, aqueous sodiumhydrogen carbonate solution and evaporated, colorless crystals of 11being obtained quantitatively.

[0186] TLC: CHCl₃:MeOH=9:1

[0187]¹H-NMR (CDCl₃; δ (ppm)): 1.65 (ddd, 1H, H-9, J_((9,9′))=13.4 Hz);2.10 (ddd, 1H, H-9′, J_((9,9′))=13.4 Hz); 2.15 (dd, 1H, H-5,J_((5,5′))=14.2 Hz); 2.40 (s, 3H, NCH₃); 2.65 (dd, 1H, H-5′,J_((5,5′))=14.2 Hz); 3.05 (ddd, 1H, H-10); 3.20 (ddd, 1H, H-10′); 3.60(d, 1H, H-12, J_((12,12′))=16.0 Hz); 3.80 (s, 3H, OCH₃); 3.90-4.05 (m,4H, O—CH₂—CH₂—O); 4.10 (d, 1H, H-12′, J_((12,12′))=16.0 Hz); 4.55 (dd,1H, H-4a); 5.65 (d, 1H. H-8, J₍₇₋₈₎=9.8 Hz); 6.15 (d, 1H, H-7,J_((7,8))=9.8 Hz); 6.55, 6.60 (AB, 2H, H-1/2)

[0188]¹³C-NMR (CDCl₃; δ ppm)): 33.2 (t, C-5); 33.8 (t, C-9); 41.7 (q,N—CH₃); 47.8 (t, C-10); 53.8 (s, C-8a); 55.5 (q, OCH₃); 60.2 (t, C-12);64.0, 65.0 (2* t, O—CH₂—CH₂—O); 87.1 (d, C-4a); 102.5 (s, C-6); 110.9(d, C-8); 121.1 (d, C-2); 125.9 (d, C-7); 128.7 (s, C-12a); 128.9 (s,C-12b); 131.8 (d, C-1); 143.8 (s, C-3a); 146.5 (s, C-3)

[0189] (±) Galanthamine-2-hydroxyethyl ether (12)

[0190] To the educt (10) (1.0 g), dissolved in 25 mL of THF and cooledto 0° C., 9 mL of a 1M solution of lithium aluminum hydride in THF wereadded dropwise over a period of 5 minutes and stirring was continued at0° C. for 30 minutes. Subsequently, the reaction mixture was refluxedfor 48 hours and cooled and 25 mL (25%) ammonia were added dropwise,after which 4 mL of the reaction mixture were extracted with 20 mL ofethyl acetate. The organic phases were dried over sodium sulfate andevaporated. Yield: 0.76 g of a yellowish oil (12)(92.9% of thetheoretical yield). Colunmn chromatography (40 g of silica gel 60,CHCl₃/2-7% of MeOH) resulted in 0.62 g of colorless foam.

[0191] Molecular weight (C₁₉H₂₄NO₄): 330.40

[0192] N-Demethylbromonarwedine ethylene glycol ketyl (13)

[0193] N-formylbromonarwedine ethylene glycol ketal (9.0 g, 21.3 mmoles)(10) is suspended in 100 mL of absolute tetrahydrofuran, treated at −15°to at most −10° C. with 28.4 mL (25.6 mmoles) of a 0.9 N solution oflithium aluminum hydride in diethyl ether and stirred at thistemperature. After 20 minutes, a further 10 mL of a 0.9 N lithiumaluminum hydride solution in diethyl ether are added dropwise andstirred for a further 20 minutes at −15° to −10° C. Subsequently, thereaction mixture is hydrolyzed with 15 mL of 2:1 mixture oftetrahydrofuran and water, the solution is concentrated in a rotaryevaporator and the residue taken up in 200 mL of water and extractedthree times with 100 mL portions of ethyl acetate. The combined organicphases are washed with a saturated, aqueous sodium chloride solution,dried (sodium sulfate) and evaporated, 6.53 g (78% of the theoreticalyield) of colorless crystals of 13 being obtained.

[0194] DC:

[0195] CHCl₃:MeOH=95:5

[0196] EtOAc:MeOH=9:1

[0197]¹H-NMR (CDCl₃; δ (ppm)): 1.70-1.85 (b, 1H tauscht D₂O, NH); 1.80(dd, 1H, H-9); 1.90 (dd, 1H, H-9′); 2.15 (dd, 1H, H-5, J_((5,5′))=16.0Hz); 2.65 (dd, 1H, H-5′, J_((5,5′))=16.0 Hz); 3.20 (ddd, 1H, H-10); 3.80(s, 3H, OCH₃); 3.85-4.10 (m, 6H, H-10′/12, HO—CH₂—CH₂—O); 4.50 (d, 1H,H-12′, J_((12,12′))=14.2 Hz); 4.60 (dd, 1H, H-4a); 5.65 (dd, 1H, H-8,J_((7,8))=9.8 Hz); 6.15 (dd, 1H, H-7, J_((7,8))=9.8 Hz); 6.85 (s, 1H,H-2)

[0198] N-Benzyl-bromonarwedine ethylene glycol ketal (14)

[0199] N-demethylbromonarwedine ethylene glycol ketal (250 mg, 0.63mmoles) (13) is mixed with 63 mg (0.63 mmoles) of triethylamine in 15 mLof absolute tetrahydrofuran and 108 mL (0.63 mmoles) of benzyl bromideare added at room temperature and the mixture is subsequently stirredfor 24 hours. The reaction mixture is treated with 50 mL of water andthe aqueous phase extracted three times with 20 mL portions of ethylacetate. The combined organic phases are washed once with saturated,aqueous sodium chloride solution, dried (sodium sulfate) and evaporated,260 mg (85% of the theoretical yield) of colorless crystals having amelting point of 118°-119° C. of 14 being obtained. TLC: EtOAc:MeOH=9:1

[0200]¹H-NMR (CDCl₃; δ (ppm)): 1.65 (ddd, 1H-9, J_((9,9))=14.2 Hz);2.05-2.30 (m, 2H, H-5, H-9′); 2.65 (dd, 1H, H-5′, J_((5,5′))=13.4 Hz);3.00-3.30 (m, 2H, H-10/10′); 3.70 (s, 2H, CH₂—Ph); 3.80 (s, 3H, OCH₃);3.90-4.20 (m, 5H, H-12, O—CH₂—CH₂—O); 4.35 (dd, 1H, H-12′,J_((12,12′))=15.1 Hz); 4.60 (ddd, 1H, H-4a); 5.70 (d, 1H, H-8,J_((7,8))=9.8 Hz); 6.25 (d, 1H, H-7, J_((7,8))=9.8 Hz); 6.85 (s, 1H,H-2); 7.25-7.30 (m, 5H, Ph)

[0201]¹³C-NMR (CDCl₃; δ (ppm)): 33.1 (t, C-5); 33.4 (t, C-9); 48.5 (s,C-8a); 50.7 (t, C-10); 55.8 (q, OCH₃); 56.4 (t, C-12); 56.9 (t, CH₂—Ph);64.2, 65.1 (2* t, O—CH₂—CH₂—O); 87.4 (d, C-4a); 102.3 (s, C-6); 113.6(s, C-1); 115.6 (d, C-8); 126.6 (s, Ph-1); 127.1 (d, C-7); 128.2, 128.9(6* d, Ph-2-6, C-2); 133.1 (s, C-12a); 137.9 (s, C-12b); 144.2 (s,C-3a); 146.3 (s, C-2)

[0202] N-Demethylbromonarwedine (15):

[0203] Method A:

[0204] See general procedure for splitting the ethylene glycolprotective group.

[0205] Method B:

[0206] N-formyl bromonarwedine ketal (10) (9.0 g, 21.3 mmoles) aresuspended in 100 mL of absolute tetrahydrofuran, treated at −25° to notmore than −20° C. with 28.4 mL (25.6 mmoles) of a 0.9N lithium aluminumhydride solution in diethyl ether and stirred at this temperature. After20 minutes, a further 10 mL (9.0 mmoles) of a 0.9N lithium aluminumhydride solution in diethyl ether are added dropwise and stirred for afurther 20 minutes at −25° to −20° C. Subsequently, the reaction mixtureis hydrolyzed with 15 mL of a 2:1 mixture of tetrahydrofuran and waterand evaporated in a rotary evaporator and the residue is taken up in 200mL of 2N hydrochloric acid and stirred for 15 minutes. The aqueous phaseis treated with 5.71 g (38.1 mmoles) of L-(+)-tartaric acid, madealkaline with concentrated aqueous ammonia and extracted three timeswith 100 mL of ethyl acetate. The combined organic phases are washedwith saturated, aqueous sodium chloride solution, dried (sodium sulfate)and evaporated, 6.53 g (78% of the theoretical yield) of colorlesscrystals of 15 being obtained.

[0207] DC:

[0208] CHCl₃:MeOH =95:5

[0209] EtOAc:MeOH=9:1

[0210]¹H-NMR (CDCl₃; δ (ppm)): 1.90-2.15 (m, 2H, H-9/9′); 2.75, 2.95(AB, 2H, H-5/5′, J_((5,5′))=16.0 Hz); 3.10-3.35 (m, 2H, H-10/10′); 3.75(s, 3H, O—CH₃); 3.90 (d, 1H, H-12, J_((12,12′))=16.4 Hz); 4.40 (d, 1H,H-12′, J_((12,12′))=16.4 Hz); 4.55 (dd, 1H, H-4a); 5.90 (d, 1H, H-8,J_((7,8))=10.7 Hz); 6.90 (s, 1H, H-2); 7.05 (d, 1H, H-7, J_((7,8))=10.7Hz)

[0211]¹³C-NMR (CDCl₃; δ (ppm)): 36.3 (t, C-5); 37.0 (t, C-9); 45.6 (s,C-8a); 49.5 (t, C-10); 51.3 (t, C-12); 55.9 (q, OCH₃); 87.9 (d, C-4a);112.5 (s, C-1); 116.0 (d, C-8); 126.6 (d, C-7); 129.6 (s, C-12a); 132.0(s, C-12b); 143.7 (s, C-3a); 144.8 (d, C-2); 146.6 (s, C-3)

[0212] Bromonarwedine (16):

[0213] Method A:

[0214] See general procedure for splitting the ethylene glycolprotective group.

[0215] Method B:

[0216] N-formyl bromonarwedine ketal (10) (9.0 g, 21.3 mmoles) aresuspended in 100 mL of absolute tetrahydrofuran, treated at −5° to nothigher than 0° C. with 10.0 mL (26.0 mmoles) of a 2.6N lithium aluminumhydride solution in tetrahydrofuran and stirred at this temperature.After 20 minutes, a further 5 mL (13.0 mmoles) of a 2.6N solution oflithium aluminum hydride in tetrahydrofuran are added dropwise andstirred for a further 20 minutes at −5° to 0° C. The solution issubsequently hydrolyzed with 15 mL of a 2:1 mixture of tetrahydrofuranand water and evaporated in a rotary evaporator and the residue is takenup in 200 mL of 2N hydrochloric acid and stirred for 15 minutes. Theaqueous phase is treated with 6.4 g (42.9 mmoles) of L-(+)-tartaricacid, made alkaline with concentrated aqueous ammonia and extractedthree times with 100 mL of ethyl acetate. The combined organic phasesare washed with saturated, aqueous sodium chloride solution, dried(sodium sulfate) and evaporated, 6.21 g (80% of the theoretical yield)of colorless crystals of 16 being obtained.

[0217] DC:

[0218] CHCl₃:MeOH=95:5

[0219] EtOAc:MeOH 9:1

[0220]¹H-NMR (CDCl₃; δ (ppm)): 1.90 (ddd, 1H, H-9, J_((9,9′))=12.5 Hz);2.25 (ddd, 1H, H-9′, J_((9,9′))=12.5 Hz); 2.45 (s, 3H, NCH₃); 2.75 (dd,1H, H-5, J_((5,5′))=17.8 Hz); 2.95-3.25 (m, 3H, H-5′/10/10′); 3.85 (s,3H, OCH₃); 3.95 (d, 1H, H-12, J_((12,12′))=16.9 Hz); 4.25 (d, 1H, H-12′,J_((12,12′))=16.9 Hz); 4.70 (dd, 1H, H-4a); 6.05 (d, 1H, H—S,J_((7,8))=9.8 Hz); 6.95 (s, 1H, H-2); 7.00 (d, 1H, H-7, J_((7,8))=9.8Hz)

[0221]¹³C-NMR (CDCl₃; δ (ppm)): 33.0 (t, C-5); 36.9 (t, C-9); 42.9 (q,NCH₃); 49.2 (s, C-8a); 53.5 (t, C-10); 56.1 (q, OCH₃); 58.9 (t, C-12);88.0 (C-4a); 114.0 (s, C-1); 116.3 (d, C-2); 127.2 (d, C-8); 127.9 (s,C-12a); 131.6 (s, C-12b); 143.9 (s, C-3a); 144.4 (d, C-7); 146.5 (s,C-3); 193.9 (s, C-6) Splitting Off of The Ethylene Glycol ProtectiveGroup (15, 16, Narwedine) empirical weight, Substance No. Educt No. R₁R₆ molecular weight 15 13 Br H Narwedin 11 H CH₃ C₁₇H₁₉NO₃ [285.35] 16110 Br CH₃ C₁₇H₁₈BrNO₃ [364.25]

[0222] Educt (5 g) is dissolved in 100 mL of 2N hydrochloric acid andheated to 100° C. for 30 minutes. After cooling, the solution is madealkaline with concentrated aqueous ammonia and the product filtered offwith suction and dried at 50° C./20 mm, or extracted with ethyl acetate,dried (sodium sulfate) and evaporated.

[0223] TLC: CHCl₃: MeOH=9:1 Substance No Name Yield Melting Point 15 91%colorless crystals 173-174° C. Narwedin Narwedin quantitative colorlesscrystals 16 Bromnarwedin quantitative colorless  75-77° C. crystals

[0224] Narwedin:

[0225] H-NMR (CDCl₃; δ (ppm)): 1.85 (ddd, 1H, H-9, J_((9,9′))=14.2 Hz);2.25 (ddd, 1H, H-9′, J_((9,9′))=14.2 Hz); 2.75 (ddd, 1H, H-5,J_((5,5′))=17.8 Hz); 3.05-3.30 (m, 3H; H-5′/10/10′); 3.70 (d, 1H, H-12,J_((12,12′))=12.5 Hz); 3.80 (s, 3H, OCH₃); 4.10 (d, 1H, H-12′,J_((12,12′))=12.5 Hz); 4.70 (b, 1H, H-4a); 6.00 (d, 1H, H-8,J_((7,8))=9.8 Hz); 6.60-6.70 (m, 2H, H-1/2); 6.95 (d, 1H, H-7,J_((7,8))=9.8 Hz)

[0226]¹³C-NMR (CDCl₃; δ (ppm)): 33.3 (t, C-5); 37.3 (t, C-9); 42.5 (q,NCH₃); 49.0 (s, C-8a); 54.1 (t, C-10); 56.0 (q, OCH₃); 60.7 (t, C-12);88.0 (d, C-4a); 111.9 (d, C-2); 122.0 (d, C-8); 127.1(d, C-1); 129.4 (s,C-12a); 130.6 (s, C-12b); 144.0 (d, C-7); 144.4 (s, C-3a); 147.0 (s,C-2); 194.4 (s, C-6) General Procedure for Reduction with L-Selectideempirical formula, Substance molecular No. Educt No. R₁ R₆ weight 4Bromformyl narwedin Br

C₁₆BrNO₃[352.24] 3 Bromnarwedin Br

C₁₇H₂₀BrNO₃[366.26] 42 41 Br

C₁₉H₂₂BrNO₃[392.30] 45 44 Br

C₂₂H₂₄BrNO₃[442.36] 46 47 H

C₂₃H_(25 NO) ₃[363.46]

[0227] Educt (100 mg) is suspended in 5 mL of absolute tetrahydrofuranand treated at −5° to 0° C. with 1.2 equivalents of a 1N solution ofL-selectide in tetrahydrofuran. After 30 minutes, the reaction mixtureis hydrolyzed with a 1:1 mixture of tetrahydrofuran and water andevaporated to dryness in a rotary evaporator, the residue being taken upin 50 mL of 2N hydrochloric acid and stirred overnight at roomtemperature. The aqueous phase is washed with 20 mL of diethyl ether andmade alkaline slowly with cooling and good stirring with concentratedaqueous ammonia, so that the product precipitates. The precipitate ispermitted to crystallize for several days in the refrigerator and thenfiltered off with suction. By extracting the filtrate with ethylacetate, a second fraction of product is recovered. The crude product ispurified by column chromatography (15 g silica gel, solvent: 9:1 mixtureof chloroform and ethanol).

[0228] TLC: CHCl₃:MeOH=9:1 Substance Melting No. Name Yield Point 4(6R)-4a,5,9,10,11,12-Hexahydro- 90% color- 1-brom-3-methoxy-6H- lesscrys- benzofuro[3a,3,2-ef][2]benzazepin- tals 6-ol 3(6R)-4a,5,9,10,11,12-Hexahydro- quanti- 76-77° C.1-brom-3-methoxy-11-methyl-6H- tative benzofuro[3a,3,2-ef][2]benzazepin-colorless 6-ol crystals 42 (6R)-4a,5,9,10,11,12-Hexahydro- 30%1-brom-3-methoxy-11-(2- propenyl)-6H-benzo-furo[3a,3,2ef][2]-benzazepin- 6-ol 45 (6R)-4a,5,9,10,11,12-Hexahydro-50% 1-brom-3-methoxy-11-(phenyl- methyl)-6H-benzofuro[3a,3,2-ef][2]-benzazepin-6-ol 46 (6R)-4a,5,9,10,11,12-Hexahydro- 80%3-methoxy-11-(phenylmethyl)-6H- benzofuro[3a,3,2-ef][2]benzazepin- 6-ol

[0229] (−)-Galanthamine Carbamates and Thiocarbamates Empirical ProductFormula R Method R C₂₄H₂₆N₂O₄[406.48] (−)-Galanthamin-phenylcarbarnate A

17 C₂₆H₂₉N₂O₄[433.53] (−)-Galanthamin-R-α-methyl- benzylcarbamate A

19 C₂₆H₂₉N₂O₄[433.53] (−)-Galanthamin-S-α-methyl- benxylcarbamate A

C₂₃H₂₃N₂O₄[456.54] (−)-Galanthamin-α-naphtylcarbarnate B

C₂₂H₃₀N₂O₄[386.49] (−)-Galanthamin-n-butylcarbamate A

21 C₂₄H₂₆N₂O₃S [422.55] (−)-Galanthamin-phenylthiocarbamate B

23 C₂₂H₃₀N₂O₃S [402.56] (−)-Galanthamin-n-butylthiocarbamate B

[0230] Method A:

[0231] Isothionate or thioisothianate (1.2 equivalents) is added underargon to a solution of 500 mg (1.74 mmoles) of (−)-galanthamine in 50 mLof absolute tetrahydrofuran and stirred for 24 hours under reflux. Thereaction mixture was evaporated and the residue purified by columnchromatography (acetone=methanol=9:1), colorless crystals beingobtained.

[0232] Method B:

[0233] Sodium hydride (95%, 68 mg, 2.62 mmoles) was added under argon toa solution of 500 mg (1.74 mmoles) of (−)-galanthamine in 15 mL ofabsolute dimethylformamide and stirred for 30 minutes at roomtemperature. Subsequently, 1.2 equivalents of isocyanate orthioisocyanate were added dropwise and stirring was continued for afurther 3 hours. The reaction mixture was poured into 150 mL of waterand extracted twice with 150 mL of ethyl acetate. The organic phaseswere washed once with 100 ii of water, dried over sodium sulfate andevaporated. The residue was purified by column chromatography(acetone:methanol=9:1), colorless crystals being obtained.

[0234] TLC: Toluene:MeOH=4:1 *α_(D)(25° C., Product Yield [% d. Th.] c= 1) melting point. [° C.] 94 (Lit.|15|: 80%) −43.6° 85-86 (Lit.|15|:85-87) 58 (Lit.|15|: 60%) −56.0° 199-203 (Lit.|15|: 203-204)  93(Lit.|15|: 100%) −57.0° 48-51 (Lit.|15|: 47-49) 17 96 −45.5° 74-77 19 99−48.1° 135-136 21 97 −22.5° 175-176 23 71 −48.5° 165-167

[0235] ¹H-NMR [CDCl₃; δ (ppm)]: Proton 17 H

-5 1.60; m 1.60; m 1.58; m 1.60; m H

-1 2.10; m 2.10; m 2.10; m 1.90; m H_(b)-5 2.20; m 2.18; m 2.15; m 2.10;m CH₃—N— 2.40; s 2.4; s 2.40; s 2.38; s H_(b)-1 2.75; br.d 2.80; br.d2.65; br.d 2.68; br.d H_(b)-6 3.10; m 3.08; m 3.05; m 3.05; m H_(a)-63.30; m 3.30; m 3.15; m 3.25; m H_(b)-8 3.70; br.d 3.68; br.d 3.65; br.d3.65; br.d CH₃—O— 3.85; s 3.85; s 3.85; s 3.80; s H_(a)-8 4.15; br.d4.15; br.d 4.10; br.d 4.10; br.d H-12a 4.55; t 4.59; m 4.50; t 4.55; tH-2 5.40; t 5.45; t 5.23; t 5.25; t H-3 5.95; dd 6.00; dd 5.90; dd 5.85;dd H-4 6.30; d 6.35; d 6.20; d 6.25; d H-9 6.60; d 6.60; d 6.55; d 6.55;d H-10 6.65; d 6.70; d 6.60; d 6.65; d diverse H 6.95 (s, 1H, —NH—) 7.35(s, 1H, —NH—) 0.9 (t, 3H, CH₃—) 1.45 (m, 3H, CH₃—) 7.0-7.3 (m, 5H, Ph)7.5-7.9 (m, 7H, Naph) 1.30 (m, 2H, CH₃—CH₂ —) 4.48 (m, 1H, —CH—) 1.42(m, 2H, (—CH₂—CH₂ —) 5.20 (s, 1H, —NH—) 3.15 (m. 2H, (—NH—CH₂ —) 7.28(m, 5H, Ar—H) 4.85 (s, 1H, —NH—) Proton 19 21 23 H_(a)-5 1.55; m 1.60; m1.65; m H_(a)-1 2.10; dd 2.00; m 2.00; m H_(b)-5 1.90; m 2.15; m 2.10; mCH₃—N— 2.40; s 2.35; s 2.38; s H_(b)-1 2.70; br.d 2.60; m 2.75; mH_(b)-6 3.02; m 3.00; m 3.05; m H_(a)-6 3.25; m 3.25; m 3.50; m H_(b)-83.65; br.d 3.60; br.d 3.70; br.d CH₃—O— 3.80; s 3.70; s 3.80; s H_(a)-84.10; br.d 4.05; br.d 4.10; br.d H-12a 4.55; t 4.50; t 4.55; t H-2 5.28;t 5.90; m 6.30; t H-3 5.90; dd 6.00; dd 5.95; dd H-4 6.20; d 6.25; d6.05; d H-9 6.55; d 6.50; d 6.55; d H-10 6.65; d 6.10; d 6.65; d diverseH 1.50 (d. 3H. CH₃—) 6.9-7.25 (d. 5H, Ph—H) 0.90 (t. 3H. CH₃—) 4.80 (m,1H, —NH—CH—CH₃) 8.40 (s, 1H, —NH—) 1.30 (m, 2H, CH₃—CH₂ —) 5.20 (s. 1H.—NH—) 1.60 (m. 2H, —CH₂—CH₂ —CH₂—) 3.25 (m. 2H. —NH—CH ₂—)

[0236] ¹³C-NMR [CDCl₃; δ (ppm)]: C-Atom  17 C-1  27.8; t  27.9; t  29.1;t  27.9; t C-5  34.1; t  34.3; t  34.2; t  34.2; t CH₃—N—  41.7; q 41.9; q  40.5; q  41.7; q C-4a  47.8; s  47.9; s  47.7; s  47.8; s C-6 53.6; t  53.7; t  53.8; t  53.6; t CH₃—O  55.6; q  55.7; q  55.5; s 55.6; s C-8  60.3; t  60.4; t  60.3; t  60.3; t C-2  63.6; d  64.0; d 62.9; d  63.2; d C-12a  86.3; d  86.3; d  86.3; d  86.3; d C-3 110.9; d111.0; d 110.9; d 111;0; d C-4 118.6; d 119.0; d 121.2; d 121.2; d C-9121.4; d 120.7; d 123.4; d 123.3; d C-10 130.4; d 128.5; d 129.8; d128.3; d C-8a 132.0; s 129.2; s 129.1; s 129.2; s C-11b 138.0; s 132.1;s 132.1; s 132.1; s C-11a 143.7; s 143.8; s 143.7; s 143.6; s C-11146.3; s 146.4; s 146.3; s 146.3; s diverse C 122.8 (d, Ar—C) 120.7;121.4; 123.0; 125.7;  13.5 (q. CH₃—CH₂—)  22.4 (q, CH₃—) 123.0 (d, Ar—C)125.9; 130.6 (d, 6 naphth.C)  19.7 (t, CH₃—CH₂—)  50.6 (d, —NH—CH—)128.7 (d, 3 Ar—C) 126.7 (s, naphth.C-8a)  27.9 (t, —CH₂—CH₂—) 125.8;127; 129.9; 129.0 (s, Ar—C) 132.7 (s, naphth.C-4a)  40.5 (t, —NH—CH₂—)(d, 5 Ar—C) 134.0 (s, naphth.C-1) 156.1 (s, —OC—NH—) 143.7 (s, Ar—C)C-Atom  19  21  23 C-1  27.9; t  27.5; t  30.9; t C-5  34.3; t  34.1; t 34.1; t CH₃—N—  41.8; q  41.8; q  41.8; q C-4a  47.8; s  47.9; s  48.0;t C-6  53.6; t  53.6; t  53.6; t CH₃—O—  55.5; q  55.0; q  55.5; q C-8 60.3; t  60.3; t  60.3; t C-2  63.1; d  71.2; d  69.7; d C-12a  86.3; d 86.1; d  86.3; d C-3 110.9; d 110.9; d 110.8; d C-4 121.2; d 120.8; d121.3; d C-9 123.3; d 121.5; d 122.7; d C-10 128.3; d 128.7; d 129.2; dC-8a 132.1; s 130.0; s 131.0; s C-11b 143.7; s 131.3; s 132.0; s C-11a143.9; s 137.7; s 143.7; s C-11 146.3; s 143.7; s 146.3; s diverse C 22.4 (q. —CH₃) 100.8-128.7 (d. 5 Ar—C)  13.6 (

. —CH₃)  50.6 (d. —NH—CH—CH₃) 129.1 (s, Ar—C)  19.9 (t. —CH₂—CH₃) 155.3(s. —OOC—NH—) 146.3 (s. OSC—NH—)  27.8 (t. —CH₂—CH₂—CH₂—)  44.9 (

. —NH—CH₂—CH₂—) 189.1 (s. —OSC—NH—)

[0237] (+)-Galanthamine Carbamates and Thiocarbamates Empirical ProductFormula Name R C₂₄H₂₆N₂O₄[406.48] (+)-Galanthamine-phenylcarbamate

18 C₂₆H₂₉N₂O₄[433.53] (+)-Galanthamin-R-α-methylbenzylcarbamate

20 C₂₆H₂₉N₂O₄[433.53] (+)-Galanthamin-S-α-methylbenzylcarbarnate

22 C₂₄H₂₆N₂O₃S [422.55] (+)-Galathamine-phenylthiocarbamate

24 C₂₂H₃₀N₂O₃S [402.56] (+)-Galanthamin-n-butylthiocarbamate

[0238] General Procedure

[0239] Sodium hydride (95%, 68 mg, 2.62 mmoles) was added under argon toa solution of 500 mg (1.74 mmoles) of (+)-galanthamine in 15 mL ofabsolute dimethylformamide and stirred for 30 minutes at roomtemperature. Subsequently, 1.2 equivalents of isocyanate orthioisocyanate were added dropwise and stirring was continued for afurther 3 hours. The reaction mixture was poured into 150 mL of waterand extracted twice with 150 mL of ethyl acetate. The organic phaseswere washed once with 150 mL of water, dried over sodium sulfate andevaporated. The residue was purified by column chromatography(acetone:methanol=9:1), colorless crystals being obtained.

[0240] TLC: Toluene:MeOH=4:1 Product Yield [% d. Th.] *α_(D)(25° C., c= 1) Melting Point [° C.] 84 +51.9° 77-80 18 42 +55.6° 58-60 20 47+56.5° 55-57 56 +43.5° 195-198 91 +42.0° 52-55 22 61 +10.4° 75-78 24 73+31.2° 122-125

[0241] (−)-N-tert.-Boc-Amino Acid Epigalaanthamine Ester EmpiricalProduct Formula Name R 25 C₂₄H₃₂N₂O₆[444,55](−)-N-t-Boc-Glycin-epigalanthaminester

26 C₃₀H₄₀N₂O₈[592,74] (−)-N-t-Boc-L-Asparaginesaure-β-benzylester-epigalanthaminester

28 C₃₃H₄₀N₂O₈[592,74] (−)-N-t-Boc-D-Asparaginesaure-β-benzylester-epigalanthaminester

29 C₂₇H₃₈N₂O₆S [518,65] (−)-N-t-Boc-L-Methionin-epigalanthaminester

31 C₂₇H₃₈N₂O₈S [518.65] (−)-N-t-Boc-D-Methionin-epigalanthaminester

32 C₃₁H₃₈N₂O₆[534.65] (−)-N-t-Boc-L-Phenylalanin-epigalanthaminester

[0242] General Procedure

[0243] (−)-Galanthamine (800 mg, 2.78 mmoles), 1.2 equivalents oft-Boc-amino acid and 876.0 mg (3.34 mmoles) of triphenyl phosphine areadded to 50 mL of absolute tetrahydrofuran. After the addition of 581.7mg (3.34 mmoles) of diethyl azodicarboxylate (DEAD), the reactionmixture was stirred for 3 hours at room temperature. After the reaction,the solution was evaporated and the oily residue was purified by columnchromatography, first in ethyl acetate, in order to separate the manyby-products with a high R_(f), and then in acetone. Upon drying invacuum, the oily product expanded to a foam, from which it then hardenedin air.

[0244] TLC: acetone:MeOH=9:1 Product Yield [% d. Th.] α_(D)(25° C., c= 1) melting point [° C.] 25 93 −187.3° 65-66 26 50 −146.6° 53-56 28 53−140.0° 63-67 29 78 −181.7° 117-119 31 62 −140.6° 126-130 32 44 −159.1°67-69

[0245] ¹H-NMR [CDCl₃; δ (ppm)]: Proton 25 26 28 H_(a)-5 1.65; m 1.65; m1.60; m H

-1 1.85; m 1.80; m 1.70; m H_(b)-5 2.18; m 2.20; m 2.15; m CH₃—N— 2.40;s 2.35; s 2.40; s H_(b)-1 2.80; m 2.80; m 2.70; m H_(b)-6 3.05; m 3.10;m 3.10; m H

-6 3.25; m 3.25; m 3.25; m H_(b)-8 3.65; br.d 3.65; br.d 3.60; br.dCH₃—O— 3.80; s 3.85; s 3.85; s H_(a)-8 4.05; br.d 4.05; br.d 4.05; br.dH-12a 4.55; t 4.60; t 4.55; t H-2 3.90; d 4.55; d 4.50; d H-3 5.70; d5.60; d 5.70; d H-4 6.15; d 6.05; d 6.10; d H-9 6.55; d 6.55; d 6.55; dH-10 6.65; d 6.65; d 6.65; d diverse H 1.45 (s, 9H, 3 × CH₃—) 1.45 (s,9H. 3 × CH₃—) 1.45 (s. 9H, 3 × CH₃—) 1.80 (t, 2H, —OOC—CH₂—) 2.90 (m,1H, —OOC—CH—) 2.90 (m. 1H, —OOC—CH—) 5.60 (s, 1H, —NH—COO—) 3.0 (d, 2H,—CH₂—COOBn) 3.0 (d, 2H, —CH₂—COOBn) 5.10 (s, 2H, —OOC—CH₂—Ph) 5.15 (s,2H, —OOC—CH₂—Ph) 5.60 (s, 1H, —NH—COO—) 5.60 (s, 1H, —NH—COO) 7.30 (m,5H, Ph—H) 7.35 (m, 5H, Ph—H) Proton 29 31 32 H_(a)-5 1.65; m 1.65; m1.65; m H

-1 1.80; m 1.80; m 1.80; m H_(b)-5 1.95; m 1.95; m 2.20; m CH₃—N— 2.10;s 2.40; s 2.40; s H_(b)-1 2.85; m 2.75; m 2.80; m H_(b)-6 3.05; m 3.05;m 3.00; m H

-6 3.25; m 3.25; m 3.25; m H_(b)-8 3.65; br.d 3.60; br.d 3.60; br.dCH₃—O— 3.85; s 3.85; s 3.85; s H_(a)-8 4.05; br.d 4.05; br.d 4.05; br.dH-12a 4.60; t 4.60; t 4.55; t H-2 4.40; m 4.40; m 4.50; m H-3 5.70; d5.70; t 5.50; t H-4 6.15; d 6.15; d 6.10; d H-9 6.55; d 6.55; d 6.55; dH-10 6.65; d 6.65; d 6.65; d diverse H 1.45 (s. 9H, 3 × CH₃—) 1.40 (s.9H. 3 × CH₃—) 1.40 (s. 9H, 3 × CH₃—) 2.10 (s. 3H, CH₃—S—) 2.10 (s, 3H.CH₃—S—) 3.10 (m. 1H. —OOC—CH—) 2.20 (m, 2H, —CH₂—CH₂ —S—) 2.15 (m, 2H.—CH₂—CH₂ —S—) 5.60 (m. 2H, —CH₂—Ph) 2.55 (m, 2H, —CH₂ —CH₂—S—) 2.50 (m.2H, —CH₂ —CH₂—S—) 5.10 (s. 1H, —NH—COO—) 2.60 (m. 1H. —OOC—CH—CH₂—) 2.60(m. 1H, —OOC—CH—CH₂—) 6.10-6.30 (m, 5H, Ph—H) 5.15 (s. 1H, —NH—COO—)5.15 (s, 1H. —NH—COO—)

[0246] ¹³C-NMR [CDCl₃; δ (ppm)]: C-Atom  25  26  28 C-1  28.1; t  29.1;t  28.9; t C-5  33.9; t  33.9; t  34.1; t CH₃—N—  41.9; q  41.8; q 42.0; q C-4a  47.9; s  47.9; s  48.0; s C-6  53.8; t  53.8; t  53.9; tCH₃—O—  55.8; q  55.8; q  55.9; q C-8  60.2; t  60.2; t  60.3; t C-2 67.4; d  68.0; d  68.0; d C-12a  87.4; d  87.4; d  87.5; d C-3 111.1; d111.1; d 111.2; d C-4 121.5; d 121.4; d 121.5; d C-9 126.6; d 126.5; d126.6; d C-10 127.4; d 128.1; d 128.3; d C-8a 128.9; s 129.0; s 129.1; dC-11b 132.3; s 132.3; s 132.4; s C-11a 143.7; s 143.8; s 143.8; s C-11146.5; s 146.5; s 146.6; s diverse C  28.1 (q, 3 × CH₃—)  28.1 (q. 3 ×CH₃—)  28.2 (q, 3 × CH₃—)  42.4 (t, —OOC—CH₂—NH—)  36.8 (t, —CH₂—)  36.9(t, —CH₂—)  79.7 (s, —O—C(CH₃)₃)  50.0 (d, —CH—)  50.1 (d, —CH—) 155.6(s, —OOC—CH₂—NH—)  66.6 (t, —O—CH₂—Ph)  66.7 (t, —O—CH₂—Ph) 169.6 (s,—NH—COO—)  79.9 (s, —O—C(CH₃)₃)  80.0 (s, —O—C(CH₃)₃) 128.2-128.4 (d, 4Ar—C) 128.3-128.5 (d, 5 Ar—C) 131.8 (d, Ar—C) 135.4 (s, Ar—C) 135.3 (s,Ar—C) 155.2 (s, —OOC—CH—) 155.1 (s, —OOC—CH—) 170.2 (s, —NH—COO— 170.2(s, —NH—COO—) 170.5 (s, —COO-Bn) 170.4 (s, —COOBn) C-Atom  29  31  32C-1  28.1; t  28.1; t  28.1; t C-5  33.9; t  34.0; t  33.9; t CH₃—N— 41.8; q  41.9; q  41.9; q C-4a  48.0; s  48.0; s  47.9; s C-6  53.8; t 53.8; t  53.8; t CH₃—O—  55.8; q  55.8; q  55.8; q C-8  60.2; t  60.2;t  60.2; t C-2  67.4; d  67.7; d  67.5; d C-12a  87.4; d  87.3; d  87.4;d C-3 111.1; d 111.1; d 111.1; d C-4 121.5; d 121.5; d 121.4; d C-9126.4; d 126.6; d 126.4; d C-10 128.4; d 128.3; d 128.2; d C-8a 129.0; s129.0; s 131.7; s C-11b 132.3; s 132.3; s 132.7; s C-11a 143.8; s 143.7;s 143.8; s C-11 146.5; s 146.5; s 146.5; s diverse C  15.4 (q. —S—CH₃) 15.4 (q, —S—CH₃) (28.1 (q, 3 × CH₃—)  28.1 (q, 3 × CH₃—)  28.1 (q. 3 ×CH₃—)  38.4 (t, —CH₂—Ph)  29.6 (t, —CH₂—CH₂—S—)  29.8 (t, —CH₂—CH₂—S—) 54.5 (d, —CH—)  32.1 (t, —CH₂—CH₂—S—)  32.1 (t, —CH₂—CH₂—S—)  79.7 (s,—O—C(CH₃)₃)  52.8 (d, —CH—)  52.8 (d, —CH—) 126.8-131.8 (d, 5 Ar—C) 79.9 (s, —O—C(CH₃)₃)  79.8 (s, —O—C(CH₃)₃) 136.9 (s, Ar—C) 155.2 (s,—OOC—CH—) 155.1 (s, —OOC—CH—) 154.9 (s, —OOC—CH—) 171.5 (s, —OOC—NH—)171.5 (s, —OOC—NH—) 171.7 (s, —OOC—NH—)

[0247] uz,11/33 (+)-N-tert.-Boc-Amino Acid-Epigalanthamine EsterEmpirical Product Formula Name R 27 C₃₃H₄₀N₂O₂[592,74](+)-N-t-Boc-L-Asparaginsäure-β-benzyester-nl epigalanthaminester

30 C₂₇H₃₃N₂O₆S [515,65] (+)-N-t-Boc-L-Methionin-epigalanthaminester

[0248] General Procedure

[0249] (+)-Galanthamine (800 mg, 2.78 mmoles), 1.2 equivalents oft-Boc-amino acid and 876.0 mg (3.34 mmoles) of triphenyl phosphine areadded to 50 mL of absolute tetrahydrofuran. After the addition of 581.7mg (3.34 mmoles) of diethyl azodicarboxylate (DEAD), the reactionmixture was stirred for 3 hours at room temperature. After the reaction,the solution was evaporated and the oily residue was purified by columnchromatography, first in ethyl acetate, in order to separate the manyby-products with a high R_(f), and then in acetone. Upon drying invacuum, the oily product expanded to a foam, from which it then hardenedin air. Product Yield [% d. Th.] α_(D)(25° C., c = 1) Melting Point [°C.] 27 75 ÷121° 130-134 30 41 ÷117° 112-115

[0250] (+)-Bromogalanthamine-Phenyl Carbamate (33)

[0251] Crude bromogalanthamine (400 mg, 1.09 mmoles) was dissolved in 50mL of absolute tetrahydrofuran, treated in an argon atmosphere with 390mg (3.28 mmoles) of phenyl isocyanate and stirred for 24 hours underreflux. The reaction mixture was evaporated and the residue purified bycolumn chromatography (EE:MeOH=3:2), 450 mg (85% of the theoreticalyield) of colorless crystals being obtained.

[0252] TLC: EE:MeOH—3:2

[0253]¹H-NMR [CDCl₃; δ (ppm)]: 1.60 (m, 1H, H_(a)-5); 2.10 (m, 1H,H_(b)-5); 2.35 (m, 1H, H_(a)-1); 2.40 (s, 3H, N—CH₃); 2.70 (br, d, 1H,H_(b)-1); 3.0 (m, 1H, H_(b)-6); 3.20 (m, 1H, H_(a)-6); 3.80 (s, 3H,CH₃O—); 3.95 (dd, 1H, H-3); 4.30 (br. d, 1H, H_(a)-8); 4.55 (t, 1H,H-12a); 5.35 (t, 1H, H-2); 5.95 (dd, 1H, H-3); 6.30 (d,1H, H-4); 6.90(s, 1H, H-10); 7.0 (s, 1H, —OOC—NH—); 7.0-7.30 (m, 5H, Ar—H).

[0254]¹³C-NMR [CDCl₃; δ(ppm)]: 27.7 (t, C-1); 34.2 (t, C-5); 42.0 (s,N—CH₃); 48.5 (s, C-4a); 53.4 (t, C-6); 56.0 (q, CH₃O—); 58.6 (t, C-8);63.6 (d, C-2); 86.6 (d, C-12a); 113.9 (s, C-9); 115.7 (d, C-3); 118.7(d, C-4); 123.2, 123.5 (d, 2 Ar—C); 127.9 (s, C-8a); 128.9 (d, C-10);130.3 (s, 3 Ar—C); 133.3 (s, C-11b); 138.0 (s, Ar—C); 144.0 (s, C-11a);146.1 (s, C-11); 153.3 (s, —OOC—NH—).

[0255] (+)-Bromogalanthamine-R-α-methylbenzyl Carbamate (34)

[0256] Crude bromogalanthamine (510 mg, 1.39 mmoles) was dissolved in 20mL of absolute THF, treated in an argon atmosphere with 615 mg (4.18mmoles) of R-(+)-α-methylbenzyl isocyanate and stirred for 2 days underreflux. The reaction mixture was evaporated and the residue purified bycolumn chromatography (EE:MeOH=4:1), 600 mg (84% of the theoreticalyield) of colorless crystals being obtained.

[0257] TLC: EE:MeOH—4:1

[0258]¹H-NMR [(CDCl₃); δ (ppm)]: 1.40 (s, 3H, CH₃—); 1.55 (m, 1H,H_(a)-5); 2.0 (m, 1H, H_(a)-1); 2.05 (m,1H, H_(b)-5); 2.35 (s, 3H,N—CH₃); 2.65 (m, 1H, H_(b)-1); 2.95 (m, 1H, H_(b)-6); 3.25 (m, 1H,H_(a)-6); 3.75 (s, 3H, CH₃O—); 3.95 (d, 1H, H_(b)-8); 4.25 (d, 1H,H_(a)-8); 4.50 (t; 1H, H-12a); 4.80 (m, —NH—CH—); 5.20 (s, 1H, —NH—CH—);5.22 (t, 1H, H-2); 5.88 (dd, 1H, H-3); 6.20 (d, 1H, H-4); 6.90 (s, 1H,H-10); 7.30 (m, 5H:, Ar—H).

[0259]¹³C-NMR [CDCl₃); δ (ppm)]: 22.1 (q, —CH—CH₃); 22.1 (s, —CH—CH₃);27.5 (t, C-1); 33.7 (t, C-5); 41.4 (q, N—CH₃); 48.1 (s, C-4a); 52.8 (t,C-6); 55.6 (q, CH₃O—); 58.0 (t, C-8); 62.7 (d, C-2); 86.2 (d, C-12a);113.4 (s, C-9); 115.3 (d, C-4); 123.6; 125.6; 126.8 (d, 3 Ar—C); 127.3(s, Ar—C); 128.1; 129.3 (d, 2 Ar—C); 132.9 (s, C-8a); 143.0 (s, C-11b);143.7 (s, C-11a); 145.7 (s, C-11); 155.0 (s, —OOC—NH—).

[0260] (+)-N-Pentyl-demethylbromogalanthamine (35)

[0261] In an argon atmosphere at room temperature, 430 mg (2.84 mmoles)of n-pentyl bromide is added dropwise to a solution of 100 mg (2.84mmoles) of crude demethylbromogalanthamine in 30 mL of absolute THF.Subsequently, the reaction mixture was stirred under reflux for 2 days.The reaction mixture was evaporated, the oily residue taken up hi 10 mLof water and adjusted with concentrated ammonium hydroxide to a pH of10, a yellow precipitate being formed. The precipitate is filtered offwith suction, washed with a little water and, after drying (becameviscous in air), purified by column chromatography(chloroform:acetone=85:15), 510 mg (43% of the theoretical yield) of abrown oil being obtained.

[0262] TLC: chloroform:acetone=85:15

[0263]¹H-NMR [CDCl₃; δ (ppm)]: 0.90 (t, 3H, —CH₃); 1.30 (m, 4H, —CH ₂—CH₂—CH₃); 1.50 (t, 2H, —N—CH ₂—); 1.55 (m, 1H, H_(a)-5); 1.98 (m, 1H,H_(a)-1); 2.15 (m, H_(b)-5); 2.30 (s, OH); 2.50 (sext., 2H, —CH₂—CH₂—CH₃); 2.65 (dd, 1H, H_(b)-1); 3.05 (m, 1H, H_(b)-6); 3,28 (m, 1H,H_(a)-6); 3.80 (s, 3H, CH₃O—); 3.95 (br. d, 1H, H_(b)-8); 4.10 (t, 1H,H-2); 4.35 (br. d, 1H, H_(a)-8); 4.55 (t, 1H, H-12a); 6.0 (dd, 1H, H-3);6.10 (d, 1H, H-4); 6.85 (s, 1H, H-10).

[0264]¹³C-NMR [CDCl₃; δ (ppm)]: 13.9 (q, —CH₃); 22.4 (t, —CH₂—CH₂—CH₃);27.1 (t, —CH₂—CH₂—CH₃); 29.4 (t, N—CH₂—CH₂—); 29.7 (t, C-1); 33.1 (t,N—CH₂—CH₂—); 48.8 (s, C-4a); 52.5 (t, C-5); 52.3(t, C-6); 56.0 (q,CH₃O—); 56.0 (t, C-8); 61.7 (d, C-2); 88.7 (d, C-12a); 114.3 (s, C-9);115.7 (d, C-3); 126.7 (d; C-4); 127.8 (d, C-10); 128.1 (s, C-8a);134.1(s, C-11b); 144.0 (s, C-11a); 145.3 (s, C-11).

[0265] O-TBDMS-N-Demethylbromogalanthamine (36):

[0266] A solution of 200 mg (0.57 mmoles) of 4.63 mg (0.63 mmoles) oftriethylamine, 38 mg (0.57 mmoles) of imidazole, 157 mg (1.14 mmoles) ofpotassium carbonate and 171 mg (1.14 mmoles) oft-butyldimethychlorosilane in 15 mL absolute tetrahydrofuran is refluxedfor 12 hours. Subsequently, the tetrahydrofuran is removed in a rotaryevaporator and the residue purified by column chromatography (15 g ofsilica gel, solvent:chloroform:MeOH=95:5), 30 mg (12% of the theoreticalyield) of an oily substance (36) being obtained.

[0267] TLC: chloroform:MeOH=9:1

[0268] H-NMR (CDCl₃; δ (ppm)): 0.09 (s, 9H, C(CH₃)₃); 0.85 (s, 6H,Si(CH₃)₂); 1.82 (dd, 1H, H-9); 1.96-2.14 (m, 2H, H-9′/5); 2.34 (ddd, 1H,H-5′); 3.31 (ddd, 1H, H-10); 3.51 (ddd, 1H, H-10′); 3.80 (s, 3H, OCH₃);3.86 (d, 1H, H-12); 4.46 (b, 1H, H-6); 4.60 (b, 1H, H-4a); 4.22 (d, 1H,H-12′); 5.98 (dd, 1H, H-8); 6.01 (d, 1H, H-7); 6.88 (s, 1H, H-2)

[0269] O-TMS-Bromogalanthamine (37):

[0270] A solution of 800 mg (2.19 mmoles) of rac. bromogalanthamine (1),260 mg mmoles) of trimethylsilyl chloride and 243 mg (2.40 mmoles) oftriethylamine in 30.1 absolute tetrahydrofuran is refluxed. After 2hours, a further 130 mg (1.2 mmoles) of trimethylsilyl chloride areadded dropwise and refluxed for one hour. Subsequently, the reactionmixture is evaporated, taken up in a little dichloromethane and purifiedover a filter column, bright yellow crystals of 37, melting at 228°-230°C., being obtained quantitatively.

[0271] TLC: chloroform:MeOH=9:1

[0272]¹H-NMR (CDCl₃; δ (ppm)): 0.10 (s, 9H, Si(CH₃)₃); 1.75 (broad d, 1HH-9); 2.00-2.20 (m, 2H, H-9′/5); 2.35-2.50 (broad d, 1H, H-5′); 2.50 (s,3H, NCH₃); 3.0-3.15 (m, 1H, H-10); 3.50 (ddd, 1H, H-10′); 3.85 (s, 3H,OCH₃); 4.20 (d, 1H, H-12, J_((12,12′))=16.0 Hz); 4.25 (b, 1H, H-6); 4.50(d, 1H, H-12′, J_((12,12′))=16.0 Hz); 4.60 (dd, 1H, H-4a); 5.90 (dd, 1H,H-8, J_((7,8))=9.8 Hz); 6.00 (dd, 1H, H-7, J_((7,8))=9.8 Hz); 6.90 (s,1H, H-2)

[0273] (−)-O-TBDMS-Bromogalanthamine (38):

[0274] A solution of 2.0 g (5.46 mmoles) of (−)-bromogalanthamine (3),1.23 g (8.20 mmoles) of t-butyldimethylchlorosilane and 0.61 g (6.00mmoles) of triethylamine in 50 mL of tetrahydrofuran is heated for 4hours at 50° C. Subsequently, the tetrahydrofuran is evaporated in arotary evaporator, the residue taken up in a little dichloromethane andpurified over a 1 cm silica gel column, 1.8 g (69% of the theoreticalyield) of amorphous, viscous substance (38) with a rotation of an α_(D)²⁰ [CHCl₃]=−66° being obtained.

[0275] TLC: chloroform:MeOH=9:1

[0276]¹H-NMR (CDCl₃; δ (ppm)): 0.05 (s, 6H, Si(CH₃)₂); 0.90 (s, 9H,SiC(CH₃)₃); 1.75-1.90 (m, 1H, H-9); 1.95-2.10 (m, 2H, H-5/9′,J_((5,5′))=16.9 Hz); 2.55 (s, 3H, NCH₃); 2.65 (dd, 1H, H-5′,J_((5,5′))=16.9 Hz); 3.00-3.15 (m, 1H, H-10, J_((10,10′))=12.5 Hz); 3.45(ddd, 1H, H-10′, J_((10,10′))=12.5 Hz); 3.85 (s, 3H, OCH₃); 4.15 (dd,1H, H-6); 4.20 (d, 1H, H-12, J_((12,12′))=16.0 Hz); 4.45 (d, 1H, H-12′,J_((12,12′))=16.0 Hz); 4.60 (b, 1H, H-4a); 5.59, 6.05 (AB, 2H, H-7/8,J_((7,8))=10.7 Hz); 6.95 (s, 1H, H-2)

[0277] O-TBDMS-Galanthamine (39):

[0278] A solution of 500 mg (1.36 mmoles) of galanthamine hydrobromide,1.37 mg (1.36 mmoles) of triethylamine, 224 mg (1.36 mmoles) ofpotassium carbonate and 244 mg (1.63 mmoles) oft-butyldimethylchlorosilane in 20 mL of absolute tetrahydrofuran and 5mL of absolute N,N-dimethylformamide is stirred for 4 hours at 60° C.Subsequently, the reaction mixture is evaporated and purified over asilica gel column, 320 mg (59% of the theoretical yield) of a yellow,oily substance (39), being obtained.

[0279] TLC: chloroform:MeOH=9:1

[0280]¹H-NMR (CDCl₃; δ (ppm)): 0.05, 0.10 (2* s, 6H, Si(CH₃)₂); 0.85,0.90 (2* s, 9H, SiC(CH₃)₃); 1.55 (ddd, 1H, H-9, J_((9,9′))=14.2 Hz);2.00-2.20 (m, 2H, H-5/9′, J_((9,9′))=14.2 Hz); 2.25-2.45 (m, 1H, H-5′);2.35 (s, 3H, NCH₃); 3.00 (ddd, 1, H-10, J_((10,10′))=11.6Hz); 3.30 (ddd,1H, H-10′, J_((10,10′))=11.6 Hz); 3.60 (d, 1H, H-12, J_((12,12′))=14.2Hz); 3.85 (s, 3H, OCH₃); 4.15 (d, 1H, H-12′, J_((12,12′))14.2 Hz); 4.25(dd, 1H, H-6); 4.55 (dd, 1H) H-4a); 5.85 (dd, 1H, H-8, J_((7,8))=9.8Hz); 6.10 (d, 1H, H-7, J_((7,8))=9.8 Hz); 6.50, 6.60 (AB, 2H, H-1/2,J_((1,2))=8.0 Hz)

[0281] N-Allyl-N-demethyl-narwedine (41):

[0282] A solution of 100 mg (0.29 mmoles) of demethylbromonarwedine(15), 38 mg (0.31 mmoles) of allyl bromide, 46 mg (0.31 mmoles) ofsodium iodide and 85 mg (0.62 mmoles) of potassium carbonate in 10 mL ofabsolute acetone is refluxed for 12 hours. Subsequently, the solution isevaporated, taken up in 2N hydrochloric acid, made alkaline withconcentrated ammonia solution and extracted with chloroform. Thecombined organic phases are washed once with saturated aqueous sodiumchloride solution, dried (sodium sulfate), filtered and evaporated, 50mg of crude product being obtained, which is purified by columnchromatography (15 g of silica gel, solvent: chloroform:MeOH=9:1), 28 mg(25% of the theoretical yield) of colorless crystals (41) beingobtained.

[0283] TLC: chloroform:MeOH=9:1

[0284]¹H-NMR (CDCl₃; δ (ppm)): 1.80-2.25 (m, 3H-599′); 2.75 (ddd, 1H,H-5′); 3.05-3.25 (m, 2H, H-10/10′); 3.78 (s, 2H, NCH₂); 3.84 (s, 3H,OCH₃); 4.00 (d, 1H, H-12); 4.55 (d, 1H, H-12′); 4.73 (b, 1H, H-4a); 5.18(dd, 2H, ═CH₂); 5.90 (dd, 1H, ═CH); 6.04 (d, 1H, H-8); 6.90 (s, 1H,H-2); 7.03 (d, 1H, H-7)

[0285](6R)-4a,5,9,10,11,12-Hexahydro-1-bromo-3-methoxy-11-(phenylmethyl)-6H-benzofuro-[3a,3,2-ef][2]benzazepin-6-one(44):

[0286] A solution of 500 mg (1.43 mmoles) of demethylbromonarwedine(15), 244 mg (1.43 mmoles) of benzyl bromide, 214 mg (1.43 mmoles) ofsodium iodide and 400 mg (2.90 mmoles) of potassium carbonate in 40 mLof absolute acetone is refluxed for 4 hours. Subsequently, the solutionis evaporated, taken up in 2N hydrochloric acid, made alkaline withconcentrated ammonia and extracted with trichloromethane. The combinedorganic phases are washed once with saturated, aqueous sodium chloridesolution, dried (sodium sulfate), filtered and evaporated, 350 mg ofcrude product being obtained, which is purified by column chromatography(15 g of silica gel, solvent: EtOAc:PE=1:1), 280 mg (45% of thetheoretical yield) colorless crystals of 44, with a melting point of135°-138° C., being obtained.

[0287] TLC: chloroform:MeOH=9:1

[0288]¹H-NMR (CDCl₃; δ (ppm)): 1.88 (dd, 1H, H-9); 2.15 (ddd, 1H, H-9′);2.55-2.80 (m, 2H, H-5/5′); 2.98-3.38 (m, 2H, H-10/10′); 3.77 (s, 2H,NCH₂); 3.86 (s, 3H, OCH₃); 4.03 (d, 1H, H-12); 4.31 (d, 1H, H-12′); 4.74(b, 1H, H-4a); 6.04 (d, 1H, H-8); 6.93 (s, 1H, H-1H, H-7); 7.21-7.46 (m,5H, Ph)

[0289]¹³C-NMR (CDCl₃; δ (ppm)): 31.6 (t, C-5); 37.0 (t, C-9); 49.4 (d,C-8a); 51.1 (t, C-10); 54.8(t, NCH₂); 56.1 (q, OCH₃); 56.8 (t, C-12);88.1 (d, C-4a); 114.1 (d; C-1); 116.4 (d, C-8); 127.1, 127.3 (2 d, C-7,Ph-4); 128.3 (d, Ph-1/2/6); 128.7 (2 d, Ph-3/5); 131.7 (s, C-12a); 138.1(s, C-12b); 143.9 (s, C-3a); 144.6 (d, C-2); 146.6 (s, C-3); 193.3 (s,C-6)

[0290](6R)-4a,5,9,10,11,12-Hexahydro-11-acetyl-1-bromo-3-methoxy-6H-benzofuro-[3a,3,2-ef][2]benzazepin-6-olacetate (48):

[0291] A solution of 300 mg (0.85 mmoles) of 4, 258 mg (2.55 mmoles) oftriethylamine in 15 mL of absolute acetone is reacted slowly at 0° C.with 200 mg (2.55 mmoles) of acetyl chloride and subsequently refluxedfor 24 hours. The solution is evaporated to dryness, taken up in 2Nhydrochloric acid and shaken 3 times with 30 mL of ethyl acetate. Thecombined organic phases are washed once with saturated aqueous sodiumchloride solution, dried (sodium sulfate), filtered and evaporated todryness. The crude product, which is contaminated with 59, is obtainedby MPLC (60 g silica gel, solvent: chloroform:MeOH=1:1), 190 mg (51% ofthe theoretical yield) of an oily substance (48) being obtained.

[0292] TLC: chloroform:MeOH=9:1

[0293]¹H-NMR (CDCl₃; δ (ppm)): 1.70 (ddd, 1H H-9); 1.80 (dd, 1H, H-9′);1.95 (ddd, 1H, H-5); 2.03, 2.12 (2s, 6H, 2 COCH₃); 2.02-2.18 (m, 1H,H-5′); 2.68 (ddd, 1H, H-10, J_((10,10′))=14.3 Hz); 3.20 (ddd, 1H, H-10′,J_((10,10′))=14.3 Hz); 3.85 (s, 3H, OCH₃); 4.33 (d, 1H, H-12,J_((12,12′))=16.9 Hz); 4.55 (b, 1H, H-6, J_((6,8))=4.8 Hz); 5.14 (d, 1H,H-12′, J_((12,12′))=16.9 Hz); 5.32 (dd, 1H, H4a,J_((4a,5))=J_((4a,5′))=5.2 Hz); 5.93 (dd, 1H, H-8, J_((7,8))=10.3 Hz,J_((6,8))=4.8 Hz); 6.15 (d, 1H, H-7, J_((7,8))=10.3 Hz); 6.92 (s, 1H,H-2)

[0294] Alkylation of N-demethylbromogalanthamine (4): (R₇,=/, Z=N)Substance No. group R₆ Name empirical formula MG 49

(6R)-4a,5,9,10,11,12-Hexahydro- 1-brom-3-methoxy-11-hexyl-6H-benxofuro[3a,3,2,-ef][2]- benzazepin-6ol C₂₂H₃₀BrNO₃ [436.40] 52

(6R)-4a,5,9,10,11,12-Hexahydro- 1-brom-3-methoxy-11-(cyanomethyl)-6H-benzofuro- [3a,3,2,-ef][2]benzazepin-6-ol C₁₈H₁₉BrN₂O₃[391.27] 51

(6R)-4a,5,9,10,11,12-Hexahydro- 1-brom-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef][2]- benzazepin-11-essigsäure- ethylesterC₂₀H₂₄BrNO₅ [438.33] 53

(6R)-4a,5,9,10,11,12-Hexahydro- 1-brom-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef][2]- benzazepin-11-essigsäureamid C₁₈H₂₁BrN₂O₄[409.29] 55

(6R)-4a,5,9,10,11,12-Hexahydro- 1-brom-3-methoxy-11-[2-(1H-isoindol-1,3(2H)-dion-2-yl)- ethyl]-6H-benzofurol[3a,3,2,-ef][2]benzazepin-6-ol C₂₆H₂₅BrN₂O₅ [525.41] 50

(6R)-4a,5,9,10,11,12-Hexahydro- 1-brom-3-methoxy-11-[2-propinyl)-6H-benzofuro[3a,3,2- ef][2]- benzazepin-6-ol C₁₉H₂₀BrNO₃[390.28] 54

(6R)-4a,5,9,10,11,12-Hexahydro- 1-brom-3-methoxy-11-[2-morpholinoethyl)-6H- benzofuro[3a,3,2- ef][2]benzazepin-6-olC₂₂H₂₂BrNOhd 3 l [465.39] 56

(6R)-4a,5,9,10,11,12-Hexahydro- 1-brom-3-methoxy-11-(3-dimethylaminopropyl)-6H- benzofuro[3a,3,2- ef][2]benzazepin-6-olC₂₁H₂₉BrN₂O₃ [437.39] 58

(6R)-4a,5,9,10,11,12-Hexahydro- 1-brom-3-methoxy-11-(3-piperidinopropyl)-6H- benzofuro[3a,3,2- ef][2]benzazepin-6-olC₂₄H₃₃BrN₂O₅ [477.45] 57

(6R)-4a,5,9,10,11,12-Hexahydro- 1-brom-3-methoxy-11-(2-pyrrolidinoethyl)-6H- benzofuro[3a,3,2- ef][2]benzazepin-6-olC₂₂H₂₉BrN₂O₃ [449.40] 42

(6R)-4a,5,9,10,11,12-Hexahydro- 1-brom-3-methoxy-11-(2-propen-yl)-6H-benzofuro[3a,3,2-ef][2]- benzazepin-6-ol C₁₉H₂₂BrNO₃ [392.30] 45

(6R)-4a,5,9,10,11,12-Hexahydro- 1-brom-3-methoxy-11-(phenyl-methyl)-6H-benzofuro[3a,3,2- ef][2]-benzazepin-6-ol C₂₃H₂₄BrNO₃ [442.36]

[0295] Method: A mixture of 500 mg (1.42 mmoles) ofN-demethylbromogalanthamine (4), 391 mg 2.84 mmoles) of potassiumcarbonate and 272 mg (1.70 mmoles) of potassium iodide are ground in amortar and triturated. Subsequently, the mixture in 20 mL of absoluteacetone is mixed with 1.2 equivalents of a halide reagent and refluxed.After the reaction is completed (TLC), the reaction mixture isevaporated and the residue taken up in 100 mL of 2N hydrochloric acid,washed with ethyl acetate, made alkaline with concentrated aqueousammonia and either the precipitate is filtered off with suction or thesolution is extracted three times with 30 mL of ethyl acetate. Theprecipitate is dried at 50° C./50 mbar, the combined organic phases arewashed once with saturated, aqueous sodium chloride solution, dried(sodium sulfate, activated charcoal), filtered and evaporated. Theproduct is purified further by column chromatography (15 g of silicagel; solvent: chloroform→chloroform:MeOH=9:1).

[0296] TLC: chloroform:MeOH=9:1 Substance Reaction Melting No. ReagentsTimes Yield Point 49 1-Bromhexane 24 h 67% oily — substance 52Chloroacetonitrile  2 h 89% color- 150-153° C. less crystals 51 Ethyl  1h quant. oily — chloroacetate substance 53 Chloroacetamide  1 h 90%color- 164-165° C. less crystals 55 N-(2-Bromethyl)- 48 h quant. yel- 88-89° C. phthalimide low crystals 50 Propargylbromide  4 h 57% oily —substance 54 N-(2-Chlorethyl)- 24 h 98% oily — morpholin * HCl substance56 (3-Chlorpropyl)- 72 h 46% oily — dimethylamin * HCl substance 58N-(3-Chlorpropyl)- 30 h 85% oily — piperidin * HCl substance 57N-(2-Chlorethyl)- 24 h 25% oily — pyrrolidin * HCl substance 42Allylbromid 80% 45 Benzylbromid 92%

[0297] ¹H-NMR (CDCl₃ [* in DMSO-d₆]; δ (ppm)): H- Atom 49 52 51 53 55H-9 1.55(d) 1.75 (ddd) 1.60 (ddd) 1.65 (ddd) 1.40 (dd) H-9′ 2.05 (ddd)2.05 (ddd) 1.90-2.05 1.90-2.10 1.90-2.30 H-5 2.00 (dd) 2.55-2.751.90-2.05 1.90-2.10 1.90-2.30 H-5′ 2.65 (dd) 2.55-2.75 2.20-2.30 2.70(ddd) 2.65 (ddd) H-10 3.05 (dd) 3.10 (ddd) 2.65 (dd) 3.10 (ddd) 2.95(dd) H-10′ 3.30 (ddd) 3.25 (ddd) 3.15 (dd) 3.40 (ddd) 3.25 (dd) NCH₂2.50 (dd) 3.65 (s) 3.40 (s) 3.20 (d) 1.90-2.30 OCH₃ 3.85 (s) 3.85 (s)3.80 (s) 3.85 (s) 3.75 (s) H-12 3.95 (d) 4.00 (d) 4.12 (d) 4.00 (d) 3.60(d) H-12′ 4.40 (d) 4.30 (d) 4.45 (d) 4.40 (d) 4.35 (d) H-6 4.15 (dd)4.15 (b) 4.16 (s) 4.15 (b) 4.05 (b) H-4a 4.60 (b) 4.60 (b) 4.60 (b) 4.60(b) 4.50 (b) H-8 6.00, 6.10 (AB) 6.05 (b) 6.00 (dd) 6.05 (s) 6.10 (d)H-7 6.00, 6.10 (AB) 6.05 (b) 6.10 (dd) 6.05 (s) 5.75 (dd) H-2 6.90 (s)6.90 (s) 6.90 (s) 6.90 (s) 7.00 (s) additional 0.90 (t, 3H, ω- — 1.30(t, 3H, 5.70, 6.95 (2* 1.90-2.30 (m, H CH₃); 120- OCH₂CH₃ ); b, 2* 1H6H, H-5/9′/ 1.35 (m 6H 4.20 (q, 2H. replace D₂O. NCH₂—CH₂): γ/δ/ε-CH₂);OCH₂ CH₃) NH₂) 7.80-7.90 (m, 1.45-1.60 (m, 4H, Ph) 2H, β-CH₂) J_((A,B))(12, 12′) = 16.9 (9, 9′) = 14.0 (7, 8) = 10.3 (5, 5′) = 16.2 (6, 8) =4.5 (Hz) (10, 10′) = 13.6 (9, 9′) = 13.4 (9, 9′) = 16.9 (7, 8) = 9.8(12, 12′) = 15.8 (12, 12′) = 16.1 (10, 10′) = 11.6 (12, 12′) = 16.0

[0298] H- Atom 50 54 56 55 57 H-9 1.70 (ddd) 1.48-1.63 1.55 (ddd) 1.45(d) 1.55 (ddd) H-9′ 1.95-2.01 1.92-2.13 2.00 (ddd) 1.95 (dd) 1.80-2.10H-5 1.95-2.01 1.92-2.13 1.65-1.83 1.95 (dd) 1.80-2.10 H-5′ 2.63 (dd)2.45-2.95 2.65 (dd) 2.58 (dd) 2.60-2.85 H-10 3.10-3.35 3.12 (ddd) 3.10(ddd) 3.00 (ddd) 3.15 (ddd) H-10′ 3.10-3.35 3.35 (ddd) 3.30 (ddd) 3.20(ddd) 3.35 (ddd) NCH₂ 3.48 (d) 2.45-2.95 2.50 (dt) 2.45 (t) 2.60-2.85OCH₃ 3.83 (s) 3.82 (s) 3.85 (s) 3.80 (s) 3.80 (s) H-12 3.98 (d) 4.01 (d)3.95 (d) 3.95 (d) 4.00 (d) H-12′ 4.36 (d) 4.39 (d) 4.45 (d) 4.35 (d)4.40 (d) H-6 4.18 (b) 4.12 (dd) 4.15 (dd) 4.13 (b) 4.13 (dd) H-4a 4.59(b) 4.59 (b) 4.60 (b) 4.58 (b) 4.60 (d) H-8 6.02 (dd) 6.02 (dd) 6.10 (d)6.08 (d) 6.00, 6.08 (AB) H-7 6.08 (dd) 6.09 (d) 6.00 (dd) 5.98 (dd)6.00, 6.08 (AB) H-2 6.92 (s) 6.90 (s) 6.85 (s) 6.90 (s) 6.90 (s)additional 2.29 (t, 1H, 2.45-2.95 (m, 1.65-1.85 (m, 1.35 (ddd, 2H,1.80-2.10 (m, H ≡CH, J_((≡CH, NCH2)) = 9H, H- 3H, H-5, N— Pip-4); 1.556H, H-5/9′/Pyr- 2.4 Hz) 5′/NCH₂ CH₂ /m CH₂—CH₂ ); (ddd, 4H, Pip- 3/4);2.60- orph-2/6); 3.72 2.18, 2.22 (2* 3/5); 1.68 (ddd, 2.85 (m, 9H, H-(t, 4H, morph- s, 6H, 2H, N—CH₂— 5′/NCH₂ CH₂ / 3/5, J_((mo3/5, mo2/6)) =N(CH₃)₂); 2.30 CH₂ ); 2.28 (dd, Pyr-2/5) 4.8 Hz (t, 2H, CH₂ - 2H, CH₂—N_(Pip)); NMe₂) 2.32 (dd, 2H,). - J_((A,B)) (≡CH, NCH₂) = (mo3/5,mo2/6) = (12, 12′) = 16.0 (NCH₂CH₂) = (9, 9′) = 13.4 (Hz) 2.4 4.8 7.3(10, 10′) = 12.5 (6, 8) = 4.5 (10, 10′) = 13.4 (5, 5′) = 10.6 (12, 12′)= 16.0 (6, 7) = 1.3 (12, 12′) = 16.1 (6, 8) = 4.6 (7, 8) = 10.0 (7, 8) =10.4 (9, 9′) = 13.4 (10, 10′) = 14.3 (12, 12′) = 15.4 (12, 12′) = 16.0

[0299] H- Atom 42 45 H-9 1.58 (ddd) 1.55 (ddd) H-9′ 1.90-2.10 2.01 (ddd)H-5 1.90-2.10 2.60-2.73 H-5′ 2.15-2.25 2.60-2.73 H-10 2.65 (ddd) 3.50(ddd) H-10′ 3.02-3.29 3.27 (ddd) NCH₂ 3.18 (d) 3.70 (s) OCH₃ 3.82 (s)3.82 (s) H-12 3.92 (d) 4.00 (d) H-12′ 4.35 (d) 4.34 (d) H-6 4.11 (b)4.14 (b) H-4a 4.59 (b) 4.64 (b) H-8 6.00 (dd) 6.02 (ddd) H-7 6.09 (d)6.14 (dd) H-2 6.90 (s) 6.90 (s) additional 5.16 (dd, 2H, 7.22-7.35 (m, H═CH₂); 5.88 5H, Ph) (ddt, 1H, ═CH) J_((A,B)) (NCH₂, ═CH) (6, 8) = 4.8(Hz) = 7.0 (7, 8) = 10.3  (9, 9′) = 14.0 (9, 9′) = 13.2 (12, 12′) = 16.5(10, 10′) = 13.0 (12, 12′) = 15.9

[0300] ¹³C-NMR (CDCl₃ [* in DMSO-d₆]; δ (ppm)): C-Atom 49 52 51 53 54C-5 29.7 (t) 29.2 (t) 29.3 (t) 29.4 (t) (t) C-9 33.1 (t) 34.5 (t) 33.6(t) 33.9 (t) (t) C-8a 48.8 (s) 48.3 (s) 48.4 (s) 48.3 (s) (s) C-10 51.5(t) 51.6 (t) 51.2 (t) 51.8 (t) (t) NCH₂ 52.5 (t) 53.7 (t) 53.4 (t) 56.3(t) (t) OCH₃ 55.9 (q) 56.1 (q) 55.7 (q) 55.8 (q) (q) C-12 56.0 (t) 57.2(t) 56.3 (t) 56.9 (t) (t) C-6 61.7 (d) 61.6 (d) 61.3 (d) 61.3 (d) (d)C-4a 88.6 (d) 88.6 (d) 88.3 (d) 88.3 (d) (d) C-1 114.3 (s) 113.9 (s)113.9 (s) 114.2 (s) (s) C-8 115.7 (d) 115.8 (d) 115.4 (d) 115.5 (d) (d)C-2 126.7 (d) 126.3 (d) 126.2 (d) 125.6 (d) (d) C-7 127.8 (d) 128.5 (d)127.8 (d) 128.4 (d) (d) C-12a 128.1 (s) 130.2 (s) 127.3 (s) 126.5 (s)(s) C-12b 134.1 (s) 134.0 (s) 133.7 (s) 133.7 (s) (s) C-3a 144.0 (s)144.5 (s) 143.9 (s) 144.2 (s) (s) C-3 145.3 (s) 145.6 (s) 145.2 (s)145.2 (s) (s) additional C 13.9 (q, ω- 115.5 (s, CN) 13.8 (q, 173 (s,CO) CH₃); OCH ₂CH₃); 22.5 (t, ε-CH₂); 60.3 (t, 26.9, 27.4 (2* OCH₂CH₃);t, γ/δ-CH₂); 170.3 (s, CO) 31.6 (t, β-CH₂)

[0301] C-Atom 56 58 57 C-5 29.4 (t) 29.4 (t) 29.6 (t) (t) (t) C-9 32.8(t) 32.8 (t) 33.2 (t) (t) (t) C-8a 48.6 (s) 48.5 (s) 48.9 (s) (s) (s)C-10 51.5 (t) 51.1 (t) 52.5 (t) (t) (t) NCH₂ 55.6 (t) 55.8 (t) 54.7 (t)(t) (t) OCH₃ 55.7 (q) 55.7 (q) 56.0 (q) (q) (q) C-12 57.3 (t) 56.8 (t)55.6 (t) (t) (t) C-6 61.4 (d) 61.4 (d) 61.7 (d) (d) (d) C-4a 83.3 (d)88.3 (d) 88.7 (d) (d) (d) C-1 114.0 (s) 113.9 (s) 114.3 (s) (s) (s) C-8115.4 (d) 115.4 (d) 115.7 (d) (d) (d) C-2 126.6 (d) 126.4 (d) 126.3 (d)(d) (d) C-7 127.6 (d) 127.6 (d) 128.1 (d) (d) (d) C-12a 127.7 (s) 127.8(s) 127.6 (s) (s) (s) C-12b 133.8 (s) 133.8 (s) 134.1 (s) (s) (s) C-3a143.8 (s) 143.7 (s) 144.3 (s) (s) (s) C-3 145.1 (s) 145.1 (s) 145.5 (s)(s) (s) additional 25.3 (t, N— 23.9, 24.2 (2* 23.2 (t, Pyr- C CH ₂CH₂);45.0 t, NCH ₂CH₂, 3/4); 53.7 (t, (q, N(CH₃)₂); Pip-4); 25.3 (t,CH₂—N_(Pyr)); 54.4 53.4 (t, Pip-3/5); 50.2 (t, Pyr-2/5) CH₂-NMe₂) (t,CH₂—N_(Pip)); 54.1 (t,)

[0302] Acylation of N-Demethylbromogalanthamine (4): (R₇=I, Z=N)Substance NO. Group: R₆ Name Empirical formula, MG 59

(6R)-4a,5,9,10,11,12-Hexahydro- 1-bromo-3-methoxy-11-acetyl-6H-benzofuro[3z,3,2- ef][2]benzazepin-6-ol C₁₈H₂₀BrNO₄ [394.27] 60

Ethyl(6R)-4a,5,9,10,11,12-Hexahydro- 1-bromo-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2- ef][2]benzazepin-11-α-oxo- acetate C₂₀H₂₂BrNO₆[452.31] 62

Methyl(6R)-4a,5,9,10,11,12-Hexahydro- 1-bromo-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2- ef][2]benzazepin-11-α-oxo- carboxylate C₁₈H₂₂BrNO₅[410.27] 61

(6R)-4a,5,9,10,11,12-Hexahydro- 1-bromo-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2- ef][2]benzazepin-11-γ-oxo- butyrate C₂₁H₂₄BrNO₆[466.34] 64

(6R)-4a,5,9,10.11,12-Hexahydro- 1-bromo-3-methoxy-11-(1-oxohexadecyl)-6H-benzofuro- [3a,3,2-ef][2]benzazein-6-ol C₃₂H₄₈BrNO₄[590.65]

[0303] A solution of 500 mg (1.42 mmoles) of N-demethylbromogalanthamine(4) and 156 mg (1.56 mmoles) of triethylamine in 20 mL of absoluteacetone is treated with 0.9 equivalents of acid halide and refluxed.After the reaction is completed (TLC), the reaction mixture isevaporated, the residue taken up in 100 mL of 2N hydrochloric acid,washed with a little acetate, made alkaline with concentrated aqueousammonia and either the precipitate is filtered off with suction or thesolution extracted three times with 30 mL of ethyl acetate. Theprecipitate is dried at 50° C./50 mbar, the combined organic phases arewashed with saturated, aqueous sodium chloride solution, dried (sodiumsulfate, activated charcoal), filtered and evaporated. The product ispurified further by column chromatography (7 g of silica gel; solvent:chloroform:MeOH=9:1)

[0304] TLC chloroform:MeOH=9:1 Substance Reaction Melting No. ReagentsTime Yield Point 59 Acetyl chloride   3 h 84% yellow 76-78° C. crystals60 Acid chloride of 1.5 h 54% yellow 66-69° C. ethyl oxalate crystals 62Metyl   1 h 93% color- 158-159° C.  chloroformate less crys- tals 61Acid chloride of 1.5 h 35% color- 53-57° C. methyl succinate less crys-tals 64 Palmityl chloride 99%

[0305] ¹H-NMR (CDCl₃ [* in DMSO-d₆]; δ (ppm)): H- Atom 59 60 62* 61 64H-9 1.79 (ddd) 1.92 (ddd) 1.60-1.90 1.75 (ddd) 1.74 (ddd) H-9′ 1.90(ddd) 2.03 (ddd) 1.60-1.90 1.94 (ddd) 2.24 (ddd) H-5 1.97 (dd) 2.25(ddd) 2.05 (dd) 2.06 (dd) 1.95 (ddd) H-5′ 2.05 (dd) 2.68 (dd) 2.40 (dd)2.45-2.70 2.45 (ddd) H-10 2.67 (ddd) 3.38 (ddd) 3.40 (dd) 2.98 (ddd)2.68 (ddd) H-10′ 3.20 (ddd) 3.63 (ddd) 3.90 (dd) 3.22 (ddd) 3.20 (ddd)OCH₃ 3.8 (s) 3.85 (s) 3.75 (s) 3.80 (s) 3.84 (s) H-12 4.33 (d) 4.25-4.454.20 (d) 4.33 (d) 4.31 (d) H-12′ 5.13 (d) 5.20 (d, Conf _(A)), 5.20 (d)5.22 (d) 5.18 (d) 5.75 (d, Conf _(B)) H-6 4.13 (b) 4.10 (b) 4.10 (b)4.12 (dd) 4.13 (dd) H-4a 4.60 (b) 4.45 (b, conf _(A)), 4.50 (b) 4.60(dd) 4.60 (b) 4.60 (b, Conf _(B)) H-8 6.03 (dd) 5.90-6.15 5.85 (dd) 6.02(dd) 6.05 (dd) H-7 5.90 (d) 5.90-6.15 6.00 (dd) 5.96 (d) 5.91 (d) H-26.94 (s) 6.90 (s) 6.85 (s) 6.90 (s) 6.90 (s) additional 2.11 (s, 3H,4.25-4.45 (m, 3.55 (s, 3H, 2.45-2.70 (m, 0.89 (t, ω-CH₃); H OCH₃); 2.30(b, 3H, H-12_(Conf) _(A/B) / COOH₃) 5H, H-5/ 1.18-1.40 (m, 1H simulatesCOOCH₂); COCH₂ CH₂ ); 22H, CH₂ ⁽⁴⁻¹⁴⁾); D₂O, OH) 1.10 (t, 3H, 3.65 (s,3H, 1.45-1.67 (m, OCH₂CH₃ ) COOCH₃) 4H, CH₂ ²⁻³⁾); 2.18 (t, 2H, COCH₂)

[0306]¹³C-NMR (DMSO-d₆; δ (ppm)): 59: 29.6 (q, COCH₃); 30.3, 36.1 (t,C-5_(Conformer A/B)); 37.9, 43.4 (t, C-9_(Conformer A/B)); 46.5, 48.8(t, C-10_(Conformer A/B)); 48.4 (s, C-8a); 51.4, 55.8 (t,C-12_(Conformer A/B)); 55.9 (q, OCH₃); 86.3, 86.5 (d,C-4a_(Conformer A/B)); 115.4 (d, C-8); 126.3, 126.4 (d,C-2_(Conformer A/B)); 127.7 (s, C-1); 128.5 (s, C-12a); 128.7 (d, C-7);133.2, 133.4 (s, C-12b_(Conformer A/B)); 144.0, 144.3 (s,C-11a_(Conformer A/B)); 146.6, 147.0 (s, C-3_(Conformer A/B)); 168.9,169.2 (s, CO_(Conformer A/B))

[0307] 62: 30.2, 30.5 (t, C-5_(Conformer A/B)); 36.5, 37.3 (t,C-9_(Conformer A/B)); 44.7, 45.0 (t, C-10_(Conformer A/B)); 48.4 (s,C-8a); 49.7, 50.4 (t, C-12_(Conformer A/B)); 52.2 (q, COOCH₃); 55.7 (qOCH₃); 59.7 (d, C-6); 86.8 (d, C-4a); 111.8, 112.1 (s,C-1_(Conformer A/B)); 115.2 (d, C-8); 125.8, 126.0 (d,C-2_(Conformer A/B)); 128.1, 128.3 (s, C-12a_(Conformer A/B)); 128.5,128.6 (d, C-7_(Conformer A/B)); 133.1 (s, C-12b); 143.9 (s, C-3a); 146.4(s, C-3); 155.2 (s, CO)

[0308] Rac. N-Boc-Bromogalanthamine (63):

[0309] To a solution of 1.0 g (2.84 mmoles) of rac.N-demethylbromogalanthamine (4) and 620 mg (2.84 mmoles) of di-t-butylpyrocarbonate in 50 mL of absolute tetrahydrofuran, 286 mg (2.84 mmoles)of triethylamine arc added dropwise and refluxed. After 15 minutes, thetetrahydrofuran is evaporated off in a rotary evaporator and the residuetaken up in 50 mL of ethyl acetate. The organic phase is washed oncewith 2N hydrochloric acid, a saturated aqueous sodium hydrogen carbonatesolution and a saturated, aqueous, sodium chloride solution, dried(sodium sulfate) and evaporated, colorless crystals of 63 being obtainedquantitatively.

[0310] TLC: EtOAc:MeOH=4:1

[0311]¹H-NMR (CDCl₃; δ (ppm)): 1.45 (s, 9H, t-Bu); 1.60 (dd, 1H, H-9);2.05 (dd, 1H, H-9′); 2.30 (ddd, 1H, H-5); 2.65 (ddd, 1H, H-5′); 3.30(ddd; 1H, H-10); 3.85 (s, 3H, OCH₃); 4.05-4.30 (r, 2H, H-6/10′); 4.10(d, 1H, H-12, J_((12,12′))=15.1 Hz); 4.60 (dd, 1H, H4a); 5.25 (d, 1H,H-12′, J_((12,12′))=15.1 Hz); 5.90 (d, 1H, H-8, J_((7,8))=8.9 Hz); 6.00(dd, 1H, H-7, J_((7,8))=8.9 Hz); 6.90 (s, 1H, H-2)

[0312] Modification of N-Substituted Galanthamine Derivatives SubstanceNo Educt. No. R₆ Educt R₆ Product R₁ Method 66 61

Br A 67 60

Br A 71 51

Br A 68 51

Br B 69 51

H C 68 60

Br D 70 55

Br E 65 59

H F

[0313] Method A:

[0314] An approximately 10% solution of the educt in 2N potassiumhydroxide is refluxed. After 1 to 3 hours, the reaction is completed andthe reaction solution is added dropwise to 2N hydrochloric acid and, inthe case of amino acids, neutralized with concentrated aqueous ammonia.The aqueous phase is extracted subsequently three times withchloroform:ethanol 9:1. The organic phase is evaporated and the crudeproduct optionally purified by column chromatography (15 g silica gelG60, solvent: MeOH/methylene chloride mixtures).

[0315] TLC: chloroform:MeOH=9:1 Substance No Name SF, MG Yield MeltingPoint 66 (6R)-4a,5,9,10,11,12- C₂₀H₂₂BrNO₆ 89% yellow 107-109° C.Hexahydro-1-brom-6- [452.31] crystals hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef][2]- benzazepin-11-γ-oxo- butyric acid 67(6R)-4a,5,9,10,11,12- C₁₃H₁₈BrNO₆ 22% red DecompositionHexahydro-1-brom-6- [424.26] crystals >120° C. hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef][2]- benzazepin-11-α-oxo- acetic acid 71(6R)-4a,5,9,10,11,12- C₁₈H₂₀BrNO₅ quant. colorless DecompositionHexahydro-1-brom-6- [410.27] crystals >200° C. hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef][2]- benzazepin-11-acetic acid

[0316] Method B:

[0317] All approximately 5% solution of the educt in absolutetetrahydrofuran is treated at 0° C. with two equivalents of a 10%solution of lithium aluminum hydride in tetroiydrofuran. After 1.5hours, the reaction solution is hydrolyzed with a 1:1 solution of waterin tetrahydrofuran, the tetrahydrofuran is evaporated off in a rotaryevaporator and the residue dissolved in 2N hydrochloric acid. After theaddition of 2.5 equivalents of tartaric acid, the solution is madealkaline with concentrated aqueous ammonia and extracted with ethylacetate. The combined organic phases are washed once with a saturated,aqueous sodium chloride solution, dried (sodium sulfate), filtered andevaporated. The crude product is purified by column chromatography (15 gsilica gel G60, solvent: chloroform:MeOH=9:1).

[0318] TLC: chloroform:MeOH=9:1 Sub- stance Melting No Name SF, MG YieldPoint 68 (6R)-4a,5,9,10,11,12- C₁₈H₂₂BrNO₄ quanti- — Hexahydro-1-brom-3-[396.29] tative methoxy-11-(2- oily sub- hydroxyethyl)-6H- stancebenzofuro[3a,3,2-ef][2]- benzazepin-6-ol

[0319] Method C:

[0320] An approximately 5% solution of the theoretical yield educt inabsolute tetrahydrofliran is treated at 0° C. with four equivalents of a10% solution of lithium aluminum hydride in tetrahydrofuran After 15minutes, heat to reflux. After 24 hours, the reaction solution ishydrolyzed with a 1:1 solution of water in tetrahydrofuran, thetetrahydrofuran is evaporated off hi a rotary evaporator, and theresidue is dissolved in 2N hydrochloric acid. After adding fiveequivalents of tartaric acid, it is made basic with concentrated hydrousammonia and extracted with ethyl acetate. The combined organic phasesare washed once with saturated aqueous sodium chloride solution, dried(Na₂SO₄), filtered and evaporated. The crude product is cleaned bycolumn chromatography (15 g silica gel G60, solvent:

[0321] CHCl₃: MeOH=9:1).

[0322] DC: CHCl₃: MeOH=9:1 Substance No. Name SF, MG yield Smp. 69(6R)-4a,5,9,10,11,12- C₁₈H₂₃NO₄ 81% oily — Hexahydro-3-methoxy-11-[317.39] Substance (2-hydroxyethyl)-6H- benzofuro[3a,3,2-ef][2]-benzazepin-6-ol

[0323] Method D:

[0324] 0.84 mL 10% lithium aluminum hydride solution (2.20 mmol) isheated in tetrahydrofuran to reflux. 100 mg (0.22 mmol) mt7 are thendissolved in absolute tetrahydrofuran and added dropwise to the boilingsolution. After 15 minutes, the reaction mixture is cooled to 0° C. andhydrolyzed with water: tetrahydrofuran 1:1. Subsequently, thetetrahydrofuran is evaporated off in a rotary evaporator, the residue isabsorbed in 50 mL 2 N hydrochloric acid, mixed with 0.80 g tartaricacid, made basic with concentrated aqueous ammonia and extracted threetimes with 30 mL ethyl acetate each. The combined organic phases arewashed once with saturated aqueous sodium chloride solution, dried(Na₂SO₄), filtered and evaporated, whereby 100 mg crude product areobtained, which is cleaned by column chromatography (15 g silica gel,solvent: CHCl₃: MeOH=9:1).

[0325] DC: CHCl₃: MeOH=9:1 Sub- stance Melting No. Name SF, MG Yieldpoint 68 (6R-4a,5,9,10,11,12- C₁₈H₂₂BrNO₄ 42% oily — Hexahydro-1-brom-3-[396.29] Substance methoxy-11-(2-hydroxy- ethyl)-6H-benzofuro-[3a,3,2-ef][2]benzazepin- 6-ol

[0326] Method E:

[0327] 170 mg (0.32 mmol) st80 and 80 mg (1.60 mmol) are heated toreflux in 10 ml absolute ethanol After 30 minutes the reaction mixtureis cooled and after 1 hour the resulting sediment is evaporated in arotary evaporator. The sediment is washed once with ethanol and theethanolic phase is subsequently spun in. The crude product is cleaned bycolumn chromatography (15 g silica gel, solvent: CHCl₃: MeOH=9:1).

[0328] DC: CHCl₃: MeOH=9:1 Sub- stance Melt. No. Name SF, MG Yield pt.70 (6R)-4a,5,9,10,11,12- C₁₈H₂₃BrN₂O₃ 70% color- 116-Hexahydro-1-brom-3- [395.30] less crys- 117° C. methoxy-11-(2-amino-tals ethyl)-6H-benzofuro- [3a,3,2- ef][2]benzazepin- 6-ol

[0329] Method F:

[0330] To 2 mL 10% lithium aluminum hydride solution in tetrahydrofuran(5.26 mmol), 50 mg (0.381 mmol)st62 in 1.5 mL absolute tetrahydrofuranare added dropwise. Subsequently, the mixture is heated to reflux for 90minutes. It is then hydrolyzed at 0° C. with water: tetrahydrofuran=1:1and the mixture is spun to dry. The residue is then absorbed in 2 Nhydrochloric acid, mixed with 1.2 g tartaric acid and made basic withconcentrated aqueous ammonia. Following that, it is extracted threetimes with 40 mL ethyl acetate each, the combined organic phases arewashed once with saturated aqueous sodium chloride solution, dried(Na₂SO₄), filtered and evaporated. The crude product is cleaned bycolumn chromatography (15 g silica gel, solvent: CHCl₃: MeOH=9:1).

[0331] DC: CHCl₃: MeOH=9:1 Substance Melt. No. Name SF, MG Yield pt. 65(6R-4a,5,9,10,11,12- C₁₈H₂₂NO₃ 76% oily — Hexahydro-1-brom-3- [300.38]substance methoxy-11-ethyl-6H- benzofuro[3a,3,2-ef][2]- benzazepin-6-ol

[0332] ¹H-NMR (CDDl₃ [* in DMSO-d₆]; δ (ppm)): H- Atom 66 67 71 68 69H-9 1.70-2.10 1.85-2.35 1.80-2.10 1.60 (ddd) 1.60 (ddd) H-9′ 1.70-2.101.85-2.35 1.80-2.10 1.90-2.10 1.90-2.10 H-5 2.40-2.80 1.85-2.35 2.25(dd) 1.90-2.10 1.90-2.10 H-5′ 2.90 (ddd) 3.30-3.70 3.00 (ddd) 2.60-2.752.60-2.75 H-10 3.25 (ddd) 3.30-3.70 3.20-3.50 3.10 (ddd) 3.15 (ddd)H-10′ 3.40 (d), 3.60 3.30-3.70 3.20-3.50 3.45 (ddd) 3.40 (ddd) (dd) NCH₂— — 3.15 (s) 2.60-2.75 2.60-2.75 OCH₃ 3.80 (s) 3.80 (s) 3.75 (s) 3.80(s) 3.82 (s) H-12 4.35 (d) 3.30-3.70 3.60 (d) 4.00 (d) 3.78 (d) H-12′5.20 (d) 4.10 (d) 4.20 (d) 4.40 (d) 4.17 (d) H-6 4.15 (b) 4.60 (b) 4.08(b) 4.12 (dd) 4.12 (dd) H-4a 4.60 (b) 4.90 (b) 4.50 (b) 4.60 (b) 4.60(b) H-8 5.90 (d) 6.15 (d) 6.10 (d) 5.95-6.10 6.10 (d) H-7 6.05 (dd) 5.90(dd) 5.30 (dd) 5.95-6.10 6.00 (dd) H-2 6.90 (s) 7.15 (s) 6.95 (s) 6.90(s) 6.55-6.70 additional 2.40-2.80 (m, 9.15 (b, 1H — 2.45 (b, 2H 2.50(b, 2H H 5H, H-5/ replaces D₂O replace D₂O, replace D₂O, COCH₂ — COOH)OH); 3.55 (t, OH); 3.55 (t, CH₂ CO) 2H, CH₂ OH) 2H, CH₂ OH); 6.55-6.70(m, 2H, H-1/2) J_((A,B)) (4a, 7) = 4.0 — — (10, 10′) = 14.3 (9, 9′) =14.1 (Hz) (6, 8) = 7.1 (12, 12′) = 16.1 (10, 10′) = 15.1 (7, 8) = 10.4(12, 12′) = 15.6 (12, 12′) = 17.0

[0333] H- Atom 70 H-9 1.80-2.15 H-9′ 1.80-2.15 H-5 1.80-2.15 H-5′2.40-2.70 H-10 3.20 (ddd) H-10′ 3.60 (ddd) NCH₂ 2.40-2.70 OCH₃ 3.80 (s)H-12 3.95 (d) H-12′ 4.50 (d) H-6 4.10 (dd) H-4a 4.55 (b) H-8 5.95-6.05H-7 5.95-6.05 H-2 6.90 (s) additional 2.40-2.70 (m, H 5H, H-5′/ NCH₂CH₂)J_((A,B)) — (Hz)

[0334] ¹³C-NMR (CDCl₃ [* in DMSO-d₆]; δ (ppm)): C-Atom 66* 68 69 70 65C-5 28.8, 30.2 (t) 29.4 (t) 29.7 (t) (t) (t) C-9 36.0, 37.8 (t) 33.2 (t)33.2 (t) (t) (t) C-8a 48.4 (s) 48.6 (s) 48.2 (s) (s) (s) C-10 43.6, 45.4(t) 51.7 (t) 51.7 (t) (t) (t) NCH₂ — 54.9 (t) 52.0 (t) (t) (t) OCH₃ 55.8(q) 55.7 (q) 55.6 (q) (q) (q) C-12 48.8, 50.4 (t) 57.6 (t) 57.6 (t) (t)(t) C-6 59.3 (d) 61.4 (d) 61.7 (d) (d) (d) C-4a 86.4, 86.6 (d) 88.3 (d)88.4 (d) (d) (d) C-1 111.0, 112.1 (s) 114.3 (s) 121.8 (d) C-8 115.3 (d)115.4 (d) 110.9 (d) (d) (d) C-2 128.4, 128.6 121.7 (d) 126.4 (d) (d) (d)(d) C-7 126.3 (d) 127.9 (d) 127.5 (d) (d) (d) C-12a 127.4 (s) 127.3 (s)128.8 (s) (s) (s) C-12b 133.2, 133.4 (s) 133.7 (s) 132.8 (s) (s) (s)C-3a 143.8, 144.2 (s) 144.0 (s) 144.0 (s) (s) (s) C-3 146.5, 146.9 (s)145.2 (s) 145.7 (s) (s) (s) additional C 27.4 (t, NCO— 56.6 (t, 56.7 (t,CH₂); 27.9 (t, CH₂OH) CH₂OH) CH₂COOH); 170.0, 170.4 (s, CON); 173.6,173.8 (s, COO)

[0335] General operating rule for splitting off bromine with zinc andcalcium chloride: Substance No. Educt R₄ R₅ R₆ SF, MG 112 4 OH H

C₁₆H₁₉NO₃[273.22] 73 52 OH H

C₁₈H₂₀N₂O₃[312.37] 74 54 OH H

C₂₂H₃₀N₂O₄[386.50] 43 42 OH H

C₁₉H₂₃NO₃[313.40] 46 45 OH H

C₂₃H₂₅NO₃[363.46] 72 64 OH H

C₃₂H₄₉NO₄[511.75] 47 44 ═O

C₂₃H₂₃NO₃[361.44]

[0336] A solution of 500 mg educt and 1.0 g calcium chloride in 50 mL50% ethanol is treated with 2.0 g freshly activated zinc powder andheated to reflux. Subsequently, the excess zinc is filtered off, washedwith methanol and the residual solution is rotated. The residue isabsorbed in 100 mL 1 N hydrochloric acid, made basic with concentratedaqueous ammonia and extracted with three times 50 mL ethyl acetate. Thecombined organic phases are washed once with a saturated aqueous sodiumchloride solution, dried (Na₂SO₄), filtered and evaporated. The crudeproduct is cleaned by column chromatography (15 g silica gel, solvent:CHCl₃: MeOH=9:1). Sub- Reac- stance tion No. Name time Yield Melt. pt.112 (6R)-4a,5,9,10,11,12- 1.5 h   93% color- 236-240° C.Hexahydro-1-brom-3- less crys- methoxy-6H- tals benzofuro[3a,3,2-ef][2]-benzazepin-6-ol 73 (6R)-4a,5,9,10,11,12- 3 h 55% color-  68-70° C.Hexahydro-3-methoxy- less crys- 11-(cyanomethyl)-6H- talsbenzofuro[3a,3,2-ef][2]- benzazepin-6-ol 74 (6R)-4a,5,9,10,11,12- 3 h80% Hexahydro-3-methoxy- 11-(2-morpholinoethyl)- 6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol 72 (6R)-4a,5,9,10,11,12- 3 h 84% color-Hexahydro-3-methoxy- less crys- 11-(1-oxohexadecyl)-6H- talsbenzofuro[3a,3,2- ef][2]benzazepin-6-ol 43 (6R)-4a,5,9,10,11,12- 3 h 96%Hexahydro-3-methoxy- 11-(2-propenyl)-6H- benzofuro[3a,3,2-ef][2]-benzazepin-6-ol 46 (6R-4a,5,9,10,11,12- 3 h 52% Hexahydro-3-methoxy-11-(phenylmethyl)-6H- benzofuro[3a,3,2-ef][2]- benzazepin-6-ol 47(6R-4a,5,9,10,11,12- 3.5 h   quantitative 159-162° C.Hexahydro-3-methoxy- orange crys- 11-(phenylmethyl)-6H- talsbenzofuro[3a,3,2-ef][2]- benzazepin-6-ol

[0337] ¹H-NMR (CDCl₃ [* in DMSO-d₆]; δ (ppm)): H- Atom 112 73 74 43 46H-9 1.70 (dd) 1.71 (ddd) 1.50 (ddd) 1.54 (ddd) 1.54 (ddd) H-9′ 1.70 (dd)1.92-2.10 1.93-2.12 1.92-2.12 1.94-2.20 H-5 2.05 (ddd) 1.92-2.101.93-2.12 1.92-2.12 1.94-2.20 H-5′ 2.30 (dd) 2.70 (ddd) 2.66 (ddd)2.60-2.75 2.71 (ddd) H-10 3.00-3.20 3.12 (ddd) 3.16 (ddd) 2.60-2.75 3.17(ddd) H-10′ 3.00-3.20 3.38 (ddd) 3.39 (ddd) 3.25 (ddd) 3.40 (ddd) NCH₂ —3.58 (s) 2.40-2.66 3.16 (d) 3.68 (s) OCH₃ 3.70 (s) 3.85 (s) 3.80 (s)3.85 (s) 3.87 (s) H-12 3.75 (d) 3.78 (d) 3.81 (d) 3.80 (d) 3.80 (d)H-12′ 3.90 (d) 4.17 (d) 4.17 (d) 4.08 (d) 4.13 (d9 H-6 4.10 (b) 4.14 (b)4.12 (b) 4.13 (b) 4.15 (dd) H-4a 4.45 (dd) 4.60 (b) 4.58 (b) 4.61 (b)4.66 (b) H-5 5.80 (dd) 6.00-6.04 5.98 (dd) 6.00 (ddd) 6.01 (ddd) H-76.05 (dd) 6.00-6.04 6.08 (d) 6.10 (dd) 6.12 (dd) H-1 6.65 (AB) 6.61-6.706.62 (AB) 6.64 (AB) 6.66 (AB) H-2 6.55 (AB) 6.61-6.70 6.58 (AB) 6.57(AB) 6.50 (AB) additional — — 2.40-2.66 (m, 5.12 (dd, 2H, 7.20-7.39 (m,H 8H, NCH₂ CH₂ / ═CH₂); 5.82 5H, Ph) Morph-2/6); (ddt, 1H, ═CH) 3.68 (t,Morph- 3/5) J_((A,B)) (5, 5′) = 13.4 (9, 9′) = 12.7 — (NCH₂, ═CH) = (1,2) = 8.2 (Hz) (7, 8) = 9.8 (10, 10′) = 14.0 6.6 (5, 5′) = 15.6 (12, 12′)= 15.1 (12, 12′) = 15.9 (6, 7) = 1.2 (6, 8) = 4.8 (6, 8) = 4.5 (7, 8) =10.2 (7, 8) = 10.3 (9, 9′) = 13.6 (12, 12′) = 15.4 (10, 10′) = 14.1 (12,12′) = 15.3

[0338] H- Atom 72 47 H-9 1.78 (ddd) 1.81 (ddd) H-9′ 2.18 (ddd) 2.16-2.48H-5 1.95 (ddd) 2.16-2.48 H-5′ 2.42 (ddd) 2.77 (dd) H-10 2.68 (ddd)3.10-3.42 H-10′ 3.18 (ddd) 3.10-3.42 NCH₂ — 3.71 (s) OCH₃ 3.82 (s) 3.86(s) H-12 3.93 (d, Konf_(A)) 3.81 (d) 4.41 (d, Konf_(B)) H-12′ 4.68 (d,Konf_(A)) 4.13 (d) 5.28 (d, konf_(B)) H-6 4.14 (b) — H-4a 4.57 (b) 4.79(b) H-8 5.93-6.08 7.01 (dd) H-7 5.93-6.08 6.06 (d) H-1 6.64-6.70, 6.70(d) 6.81-6.88 H-2 6.64-6.70, 6.52 (d) 6.81-6.88 additional 0.89 (t,ω-CH₃); 1.18-1.38 (m, 7.21-7.46 (m, 5H, Ph) H 22H, CH₂ ⁽⁴⁻¹⁴⁾);1.48-1.65 (m, 4H, CH₂ ⁽²⁻³⁾); 2.06 (t, 2H, COCH₂) J_((A,B)) — (1, 2) =8.1 (Hz) (4a, 5/5′) = 3.8 (4a, 8) = 1.9 (5, 5′) = 17.8, (7, 8) = 10.4,(12, 12′) = 15.6

[0339] ¹³C-NMR (CDCl₃ [* in DMSO-d₆]; δ (ppm)): C-Atom 112 C-5 30.6 (t)(t) (t) (t) (t) C-9 33.5 (t) (t) (t) (t) (t) C-8a 48.1 (s) (s) (s) (s)(s) C-10 46.3 (t) (t) (t) (t) (t) NCH₂ — OCH₃ 55.5 (q) (q) (q) (q) (q)C-12 52.8 (t) (t) (t) (t) (t) C-6 59.7 (d) (d) (d) (d) (d) C-4a 86.7 (d)(d) (d) (d) (d) C-8 111.1 (d) (d) (d) (d) (d) C-7 119.5 (d) (d) (d) (d)(d) C-2 121.0 (d) (d) (d) (d) (d) C-1 127.4 (d) (d) (d) (d) (d) C-12a132.9 (s) (s) (s) (s) (s) C-12b 133.8 (s) (s) (s) (s) (s) C-3a 142.9 (s)(s) (s) (s) (s) C-3 146.3 (s) (s) (s) (s) (s) additional C —

[0340] C-Atom 47 C-5 (t) (t) (t) (t) 32.5 (t) C-9 (t) (t) (t) (t) 36.9(t) C-8a (s) (s) (s) (s) 48.8 (s) C-10 (t) (t) (t) (t) 51.5 (t) NCH₂56.4 (s) OCH₃ (q) (q) (c) (q) 55.6 (q) C-6 (d) (d) (d) (d) 194.0 (s)C-4a (d) (d) (d) (d) 87.6 (d) C-8 (d) (d) (d) (d) 111.5 (d) C-7 (d) (d)(d) (d) 126.8 (d) C-2 (d) (d) (d) (d) 144.1 (d) C-1 (d) (d) (d) (d)121.7 (d) C-12a (s) (s) (s) (s) 129.3 (s) C-12b (s) (s) (s) (s) 138.2(s) C-3a (s) (s) (s) (s) 143.6 (s) C-3 (s) (s) (s) (s) 146.6 (s)additional C 126.7 (d, Ph-4); 127.8 (s, Ph-1); 127.9 (d, Ph- 2/6); 128.5(d, Ph-3/5)

[0341] O-TOS-Narwedine oxime (75):

[0342] A suspension of 1.05 g (3.51 mmol) narwedine oxime (76,77) in 20mL absolute pyridine[ep] is treated with 1.33 g (7.03 mmol)p-toluolsulfonic acid chloride and stirred for 20 hours at roomtemperature. The reaction mixture is subsequently poured over 100 mLwater and extracted with 50 mL ethyl acetate. The combined organicphases are washed once with a saturated aqueous sodium chloridesolution, dried (Na₂SO₄, active carbon), filtered and evaporated. Thecrude product is cleaned by column chromatography (50 g silica gel,solvent CHCl₃=>CHCl₂: MeOH=9:1), whereby 1.27 g (80% of the theoreticalyield.) yellow crystals with a melting point of 78-79° C. are obtainedat 75.

[0343] DC: CHCl₃: MeOH=9:1

[0344]¹H-NMR (CDCl₃; δ (ppm)): 1.55-1.65, 1.80-1.95 (2* m, 2HH-9/9′Conformer_(A/B); 2.05-2.25 (m, 1H, H-50Conformer_(A/B)); 2.40,2.43 (2* s, 6H NCH₃, Ph—CH₃); 2.50-2.70 (m, 1H, H-5′_(Conformer A/B));2.95-3.25 (m, 1H-10_(Conformer A/B));3.60 3.85 (m, 2H,H-10′/12_(Conformer A/B)); 4.00-4.25 (m, 1H-12′_(Conformer A/B)); 4.55(b, 1H, H-4a_(Conformer A/B)); 6.15, 7.10 (2* d, 1H,H-8_(Conformer A/B)); 6.40, 7.65 (2* d, 1H, H-7_(Conformer A/B));6.50-6.70 (m, 2H-1/2_(Conformer A/B)); 7.20-7.35 (m, 2H,Ph-3/5_(Conformer A/B)); 7.75-7.90 (m, 2H, Ph-2/6_(Conformer A/B))

[0345]¹³C-NMR (DMSO-d₆; δ (ppm)): 21.1 (q, Ph—CH₃); 23.9 (t, C-5); 31.6(t, C-9); 40.6 (q, NCH₃); 48.7 (s, C-8a); 52.9 (t, C-10); 55.5 (q,OCH₃); 59.2 (t, C-12); 84.3 (d, C-4a); 111.9 (d, C-2); 118.6, 121.6 (d,C-8_(Conformer A/B)); 125.5, 128.0 (d, C-7_(Conformer A/B)); 128.4 (d,Ph-2/6); 130.0 (d, Ph-3/5); 131.8 (s, C-12a); 136.1 (s, Ph-1); 137.5 (s,C-12b); 138.7 (d, C-1); 143.1 (s, C-3a); 145.4 (s, C-3); 145.8 (s,Ph-4); 159.8 (s, C-6)

[0346] rac., (−)- and (+)-)-methylnarwedine oxime (78, 79):

[0347] A solution of 300 mg (1.05 mmol) narwedine in 10 mL ethanol istreated with 88 mg (1.05 mmol) O-methylhydroxylamine and 53 mg (0.53mmol) potassium bicarbonate and heated for 4 hours to reflux.Subsequently, the reaction mixture is evaporated, the residue isabsorbed in 50 mL 1 N hydrochloric acid, made basic with concentratedaqueous ammonia and extracted 3 times with 30 mL ethyl acetate each. Thecombined organic phases are washed once with a saturated aqueous sodiumchloride solution, dried (Na₂SO₄), filtered and evaporated, wherebyquantitatively viscous substances (with a rotation of a_(D)²⁰[CHCl₃]=a_(D) ²⁰[CHCl₃]=−152° for 78 and/or a_(D) ²⁰[CHCl₃]=+108° for79) are obtained at 78/79.

[0348] DC: CHCl₃: MeOH=9:1

[0349]¹H-NMR (CDCl₃; δ (ppm)): 1.70 (ddd, 1H, H-9); 2.20 (ddd, 1H,H-9′); 2.30-2.45 (m, 1H, H-5); 2.40 (s, 3H, NCH₃); 2.70 (ddd, 1H, H-5′);3.00-3.35 (m, 2H, H-10/10′); 3.65, 3.70, 4.00, 4.10 (4* d, 2H,H-12_(Conformer A/B)/12′_(Conformer A/B)); 3.80 (s, 3H, OCH₃); 3.85,3.90 (2* s, 3H, N—OCH_(3 Conformer A/B)); 4.60 (b, 1H, H-4a); 6.15,6.20, 6.75 (s, d, d, 2H, H-7/8_(Conformer A/B)); 6.55-6.70 (m, 2H,H-1/2)

[0350] Narwedine Imine (80):

[0351] A solution of 100 ng (0.35 mmol) narwedine in 10 mL 7 Nmethanolic ammonia is heated to reflux in a glass autoclave for 10 hoursat 100° C. Subsequently, the excess methanol is evaporated off in arotary evaporator, whereby quantitatively colorless crystals with amelting point of 105-110° C. are obtained at 80.

[0352] DC: CHCl₃: MeOH=9:1

[0353]¹H-NMR (CDCl₃ [formation of narwedine and decomposition productsduring measuring] δ (ppm)): 1.80 (ddd, 1H-9); 2.00-2.35 (m, 2H, H-5/9′);2.45 (s, 3H, NCH₃); 2.80 (ddd, 1H, H-5′); 3.00-3.35 (m, 2H, H-10/10′);3.70 (d, 1H, H-12); 3.80 (s, 2H, OCH₃); 4.05 (d, 1H, H-12′); 4.65 (b,1H, H4a); 6.15 (d, 1H, H-8); 6.45 (d, 1H, H-7); 6.55-6.70 (m, 2H, H-1/2)

[0354] rac., (+)- or (−)-narwedine oxime (76, 77):

[0355] 1.0 g (3.51 mmol) narwedine, 266 mg (3.86 mmol) hydroxylaminehydrochloride and 193 mg (1.93 mmol) potassium bicarbonate are heated toreflux in 30 mL 96% ethanol. The reaction mixture is spun in after 3hours, the residue is absorbed in 50 mL 2 N hydrochloric acid and theproduct is precipitated with concentrated aqueous ammonia. Afterovernight crystallizing a first fraction of 0.81 g (81% of thetheoretical yield.) is obtained. After extraction of the theoreticalyield mother fluid with three times 30 mL ethyl acetate a secondfraction is obtained, whereby quantitatively colorless crystals with amelting point of 170-171° C. are obtained at 76, 77. a_(p) ²⁰[CHCl₃ eeafter CE* (−)-Narwedine oxime (77) −79° 20% (+)-Narwedine oxime (76)+126° 12%

[0356]¹H-NMR (CDCl₃; d(ppm)): 1.70 (dd, 1H, H-9, J_((9,9′))=13.4 Hz);2.20 (ddd, 1H, H-9′, J_((9,9′))=13.4 Hz); 2.40 (s, 3H, NCH₃); 2.45 (dd,1H, H-5, J_((5,5′))=16.9 Hz); 3.10 (m, 2H, H-5′, J_((5,5′))=16.9 Hz);3.30 (ddd, 1H, H-10, J_((10,10)′)=14.2 Hz); 3.75 (d, 1H, H-12,J_((12,12′))=16.0 Hz); 3.80 (s, 3H, OCH₃); 3.85 (dd, 1H, H-10′,J_((10,10′))=14.2 Hz); 4.10 (d, 1H, H-12′, J_((12,12′))=16.0 Hz); 4.65(b, 1H, H-4a); 6.20 (b, 2H, H-7/8); 6.55-6.65 (m, 2H, H-1/2)

[0357]¹³C-NMR (DMSO-d₆; d(ppm)): 22.3 (t, C-5); 32.8 (t, C-9); 41.2 (q,NCH₃); 48.7 (s, C-8a); 53.1 (t, C-10); 55.5 (q, OCH₃); 59.5 (t, C-12);85.9 (d, C4a); 111.6 (d, C-8); 121.1 (d, C-2); 122.5 (d, C-7); 129.5 (s,C-12a); 130.7 (d, C-1); 132.5 (s, C-12b); 143.1 (s, C-3a); 145.8 (s,C-3); 150.1 (s, C-6)

[0358] Conversion of narwedine with hydrazines and hydrazides: SubstanceEmpirical No. Rest R₄R₅ Name formula, MG 81

4a,5,9,10,11,12-Hexahydro-3- methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-on 2- Methylhydrazone formic acid-2-C₁₈H₂₃N₃O₂ [313.40] 84

{4a,5,9,10,11,12-hexahydro-3- methoxy-11-methyl-6H-benzofuro[3a,3,2-ef3][2]- benzazepin-6-yliden}hydrazide C₁₈H₂₁N₃O₃[327.39] 83

4a,5,9,10,11,12-Hexahydro-3- methoxy-11-methyl-6H- benzofuro[3a,3,2-ef][2]benzazepin-6-on 2-(2- Hydroxyethyl)hydrazone C₁₉H₂₅N₃O₃ [343.43]86

4-methylbenzenesulfonic acid-2- {4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H- benzofuro[3a,3,2-ef][2]-benzepin-6-yliden}hydrazide pyrocarbonic acid-t-butylester-2-C₂₄H₂₇N₃O₄S [453.56] 85

{4a,5,9,10,11,12-hexahydro-3- methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]- benzazepin-6-yliden}hydrazide pyrocarbonicacid-2- C₂₂H₂₉N₃O₄ [399.49] 89

{4a,5,9,10,11,12-hexahydro-3- methoxy-11-methyl-6H-beazofuro[3a,3,2-ef3][2]- beazazepin-6-yliden}hydrazide C₁₉H₂₁N₃O₅[371.40] 82

4a,5,9,10,11,12-Hexahydro-3- methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]- benzazepin-6-on 2,2- DimethylhydrazoneC₁₉H₂₅N₃O₂ [327.43] 88

2-{4a,5,9,10,11,12-Hexahydro-3- methoxy-11-methyl-6H-benzofuro[3a,3,2-ef3][2]- benzazepin-6-yliden}- hydrazincarboximidamideC₁₈H₂₃N₅O₂ [341.42] 90

4a,5,9,10,11,12-Hexahydro-3- methoxy-11-methyl-6H- benzofuro[3a,3,2-ef][2]benzazepin-6-on Hydrazone carbamic acid-2- C₁₇H₂₁N₃O₂ [299.38] 87

{4a,5,9,10,11,12-hexahydro-3- methoxy-11-methyl-6H-benzofuro[3a,3,2-eq][2]- benzazepin-6-yliden}hydrazide C₁₈H₂₂N₄O₃[342.40]

[0359] Method: A solution of 500 mg (1.75 mmol) narwedine and 1.1 to 1.2equivalents N-alkylhydrazone or acid hydrazide, respectively, in 10 mLethanol is treated with 0.25 equivalents (43 mg, 0.44 mmol) concentratedsulfonic acid and heated to reflux. The reaction mixture is thenevaporated, the residue is absorbed in 50 mL 1 N hydrochloric acid, madebasic with concentrated aqueous ammonia and the resulting precipitate isevaporated hi a rotary evaporator or the aqueous phase is extractedthree times with 30 mL each of ethyl acetate The precipitate is dried at50° C./50 mbar, the combined organic phases are washed once with asaturated aqueous sodium chloride solution, dried (Na₂SO₄), filtered andevaporated.

[0360] DC: CHCl₃: MeOH=9:1 Substance Reaction Melting No. Reagent equ.H₂SO₄ time Yield point 81 Methylhydrazin; 0.25  4 h 76% yellow crystals 97-99° C. 84 Ameisensäurehydrazide; 48 h 63% yellow crystals 145-148°C. 0.0 83 2-Hydrazinoethanol; 30 h 61% yellow crystals 100-105° C. 0.086 p-Toluolsulfon-  6 h 97% colorless 210-212° C. säurehydrazid; 0.25crystals 85 t-Butylcarbazat; 0.25  4 h quantitative color- Tranformationat less crystals 155-160° C., decomposition >200° C. 89Oxalsäureethylester- 30 h 64% yellow crystals 189-191° C. hydrazide;0.25 82 N,N-Dimethylhydrazin; 12 h 78% oily substance — 0.25 88Aminoguanidin 20 h quantitative yellow 112-113° C. Hydrogencarbonat; 0.0crystals 90 10 Äqu.  2 h 94% oily substance — Hydrazinhydrat; 2.5 87Semicarbazid  4 h 88% colorless decomposition ab Hydrochlorid; crystals(Lit. [ ] % d. 225° C. (Lit. [ ] Zers. 0.5 Äqu. KHCO₃ Th.) at ° C.)

[0361] ¹H-NMNR (CDCl₃ [* in DMSO-d₆]; δ (ppm)): H Atom 81 84 83 86 85H-9 1.75 (ddd) 1.70 (dd) 1.70 (ddd) 1.80 (ddd) 1.70 (ddd) H-9′ 2.10-2.352.20 (dd) 2.20 (ddd) 2.15 (ddd) 2.20 (ddd) H-5 2.10-2.35 2.50 (dd) 2.35(dd) 2.50 (b) 2.35-2.45 H-5′ 2.90-3.30 3.00-3.30 2.70 (ddd) 3.15 (dd)2.75 (ddd) H-10 2.90-3.30 3.00-3.30 3.00-3.40 3.25-3.45 3.00-3.35 H-10′2.90-3.30 3.40 (dd) 3.00-3.40 3.25-3.45 3.00-3.35 NCH₃ 2.45 (s) 2.45 (s)6.65 (s) 2.40 (s) 2.40 (s) OCH₃ 3.85 (s) 3.85 (s) 3.80 (s) 4.10 (s) 3.80(s) H-12 3.70 (d) 3.70 (d) 3.68 (d) 3.58 (d) 3.70 (d) H-12′ 4.10 (d)4.05 (d) 4.07 (d) 4.30 (d) 4.10 (d) H-4a 4.70 (b) 4.70 (b) 4.70 (b) 4.60(b) 4.15 (b) H-8 5.96 (d) 6.10-6.40 6.16 (d) 6.00 (d) 6.35 (d) H-7 6.98(dd) 6.10-6.40 5.98 (dd) 6.32 (d) 6.20 (dd) H-1/2 6.48-6.68 6.50-6.706.55-6.65 6.55-6.78 6.55-6.70 additional 2.50 (s, 3H, N— 8.65 (b 1H,3.00-3.40 (m, 3.70 (s, 3H, 1.50 (s, 9H, H NCH₃); CHO); 10.40 6H,H-10/10′, PhCH₃); 7.36 C(CH₃)₃); 7.70 more conform B: (b, 1H, replacesN—CH₂—CH₂—O); (d, 2H, Ph-3/5); (b, 1H replaces 5.80-6.06 (m, D₂O, NH)more conform B: 7.76(d, 2H, D₂O, NH) 2H, H-7/8) 4.07, 4.14 (2* Ph-2/6)d, 2H, H- 12/12′); 6.38 (dd, 1H, H-8); 6.70 (dd, 1H, H-7) J_((A,B)) (7,8) = 10.2 (12, 12′) = 14.2 (7, 8) = 14.4; (7, 8) = 10.2; (7, 8) = 8.9;(Hz) (12, 12′) = 15.2; (12, 12′) = 16.0 (12, 12′) = 13.4 (12_(B),12_(B)′) = 7.2

[0362] H- Atom 89 82 88 90 87 H-9 1.85 (ddd) 1.80 (ddd) 1.65 (dd) 1.70(dd) 1.65 (dd) H-9′ 2.30 (ddd) 2.20 (ddd) 2.00-2.40 2.15-2.40 2.20 (ddd)H-5 2.75 (dd) 2.35 2.50 2.00-2.40 2.15-2.40 2.50 (dd) H-5′ 3.05-3.352.75 (ddd) 2.75 (ddd) 2.65 (ddd) 2.70 (dd) H-10 3.05-3.35 3.00-3.35 2.95(dd) 3.05 (ddd) 2.95-3.20 H-10′ 3.05-3.35 3.00-3.35 3.10-3.30 3.25 (ddd)2.95-3.20 NCH₃ 2.45 (s) 2.55 (s) 2.25 (s) 2.40 (s) 2.35 (s) OCH₃ 3.85(s) 3.85 (s) 3.70 (s) 3.80 (s) 3.75 (s) H-12 3.75 (d) 3.70 (d) 3.58 (d)3.70 (d) 3.55-3.70 H-12′ 4.10 (d) 4.10 (d) 4.06 (d) 4.08 (d) 3.95-4.15H-4a 4.70 (b) 4.65 (b) 4.58 (b) 4.20 (b) 4.60 (b) H-8 6.05 (d) 6.15-6.406.00-6.15 6.05 (d) 5.95 (d) H-7 6.95 (d) 6.15-6.40 6.00-6.15 6.20 (d)6.90 (d) H-1/2 6.60-6.75 6.55-6.75 6.55, 6.68 (AB) 6.55-6.70 6.50-6.65additional 2.40, 2.50 (2*s, 5.55-5.90 (b, 5.30 (b, 2H more conform B: H6H, N(CH₃)₂) 4H replace replace D₂O, 3.55-3.70 (m, D₂O, NH); NH₂); 1H,H-12_(A/B)); more conform B: more conform B: 3.95-4.15 (m, 6.95 (d, 1H,6.35 (d, 1H, H- 1H, H-12′_(A/B)); H-7) 8); 6.95 (d, 1H, 4.65 (b, 1H, H-H-7) 4a_(B)), 6.10 (s, 1H, H-8_(B)); 6.50- 6.65 (m, 3H, H-1/2/7_(B))J_((A,B)) (5, 5′) = 17.8; (12, 12′) = 16.0 (1, 2) = 8.2; (12, 12′) =15.1 (5, 5′) = 16.9 (Hz) (7, 8) = 10.5; (12, 12′) = 15.3 (7_(A), 8_(A))= 9.8 (9, 9′ = 13.7; (12, 12′) = 15.4

[0363]¹³C-NMR (CDCl₃ [* in DMSO-d_(6]); d(ppm)) 86: 24.8 (t, C-5); 31.7(t, C-9); 41.2 (q, NCH₃); 53.0 (t, C-10); 47.8 (s, C-8a); 55.5 (q,OCH₃); 58.8 (t, C-12); 85.5 (d, C-4a); 111.9 (d, C-8); 122.3 (d, C-2);125.0 (d, C-7); 125.2 (s, Ph-1); 127.5 (d, Ph-2/6); 129.5 (d, Ph-3/5);132.2 (d, C-1); 132.3 (s, C-12a), 136.2 (s, C-12b); 143.3 (s, C-3a);143.8 (s, Ph-4); 145.8 (s, C-3); 149.8 (s, C-6)

[0364] 85 *: 24.5 (t, C-5); 28.1 (q, C(CH₃)₃); 32.4 (t, C-9); 41.2 (q,NCH₃); 48.2 (s, C-8a); 53.1 (t, C-10); 55.5 (q, OCH₃); 59.3 (t, C-12);79.4 (s, C(CH₃)₃); 86.0 (d, C-4a); 111.7 (d, C-8); 121.5 (d, C-2); 125.5(d, C-7); 131.2 (d, C-1); 128.5 (s, C-12a); 132.5 (s, C-12b); 143.3 (s,C-3a); 145.6 (s, C-3); 145.8 (s, C-6); 153.0 (s, CO)

[0365] (−)-Alkyl Galanthamine Halogenide Empirical Product FormulaDesignation R C₂₂H₃₁BrNO₃[401.95] (−)-Pentylgalanthaminium-bromide

91 C₂₁H₃₀ClN₂O₃[358.49] (−)-Dimethylaminoethylgalanthaminium-chloride

92 C₂₃H₃₂ClN₂O₃[419.97] (−)-2-Pyrrolidin-N-ethylgalanthaminium-chloride

93 C₂₃H₃₂ClN₂O₄[435.97] (−)-2-Morpholin-N-ethylgalanthaminium-chloride

94 C₂₄H₃₄ClN₂O₃[434.0]  (−)-2-Piperidin-N-ethylgalanthaminium-chloride

95 C₂₅H₃₆ClN₂O₃[448.03] (−)-3-Piperidin-N-propylgalanthaminium-chloride

C₂₀H₂₆BrNO₃[407.33] (−)-Allylgalanthaminium-bromide

[0366] General Procedure:

[0367] 800 mg (2.78 mmol) (−)-galanthamine and 3.84 g (27.8 mmol)potassium carbonate were presented in 100 mL acetone. After adding 1.5equivalents of halogenide and a spatula tip of potassium iodide, thereaction mixture was stirred under reflux for 24-36 hours. The potassiumcarbonate was then evaporated in a rotary evaporator and the filtratewas evaporated. The oily residue was finally cleaned by columnchromatography in a mixture of trichloromethane and anionically methanol(9:1).

[0368] DC: CHCl₃: MeOH (10% NH₃)=9:1 Product Yield [% d. Th.] *α_(D)(25°C., c = 1) Melting Point [° C.] 71 −83.7° 130-132 91 72 −46.6° 148-15092 43 −62.5° 120-125 93 94 −52.3° 225-229 94 48 −70.8° 136-140 95 70−71.5° 126-131 41 −74.3° 188-192

[0369] ¹H-NMR [DMSO-d₆; δ (ppm)]: Proton 91 92 93 H_(a)-5 2.10; m 2.10;m 2.00; m 2,00; m H

-1 2.20; m 2.30; m 2.50; m 2.20; m H_(b)-5 2.30: m 2.45; m 2.55; m 2.50;m CH₃—N— 3.50; s 2.85; s 2.95; s 3.00; s H_(b)-1 2.70; br.d 2.50; m2.65; m 2.90; m H_(b)-6 4.25; m 3.10; m 3.10; m 3.50; m H_(a)-6 4.30; m3.25; m 3.80; m 3.60; m H_(b)-8 4.90; br.d 4.50; br.d 4.15; br.d 4.15;br.d CH₃—O— 3.85; s 3.80; s 3.75; s 3.80; s H_(a)-8 5.25; br.d 5.05;br.d 5.15; br.d 5.10; br.d H-12a 4.70; t 4.70; t 4.65; t 4.70; t H-24.20; m 4.10; m 3.90; m 3.90; m H-3 6.15; dd 5.95; dd 6.00; dd 6.05; ddH-4 6.45; d 6.20; d 6.15; d 6.20; d H-9 6.70; d 6.80; d 6.70; d 6.75; dH-10 7.10; d 6.90; d 6.85; d 6.85; d diverse H 0.95 (t, 3H, CH₃—) 3.35(s, 6H, 2 × 1.75 (m, 4H, 2 × CH₂*) 2.50-2.60 (m, 6H, 1.35-1.50 (m, 4H,CH₃—N—) 2.60 (m, 2H, —CH₂—N—) 2 × —CH₂—N—*) 2 × —CH₂—) 3.40 (t, 2H,—CH₂—N—) 3.10 (m, 4H, 2 × 2.55 (m, 2H, —CH₂—N—) 1.70 (m, 2H, —CH₂—) 3.90(t, 2H, —N—CH₂—) —CH₂—N—*) 3.0-3.20 (m, 6H, 3 × 2.0 (t, 2H, —N—CH₂—)3.80 (m, 2H, —N—CH₂—) —O—CH₂—*) *⁾Pyrrolidin *⁾Morpholin Proton 94 95H_(a)-5 2.00; m 1.45; m 2.13; m H_(a)-1 2.20; m 2.00; m 2.25; m H_(b)-52.50; m 2.15; m 2.50; m CH₃—N— 3.15; s 2.85; s 2.75; s H_(b)-1 2.65;br.d 2.45; br.d 2.50; m H_(b)-6 3.00; m 3.30; m 3.35; m H_(a)-6 3.10; m3.60; m 3.35; m H_(b)-8 5.15; br.d 4.45; br.d 4.50; m CH₃—O— 3.85: s3.80; s 3.75; s H_(a)-8 5.40; br.d 5.05; br.d 5.05; br.d H-12a 4.65; t4.65; t 4.65; t H-2 4.15; m 4.10: m 4.15; m H-3 6.15; dd 5.95; dd 5.90;dd H-4 6.40; d 6.20; d 6.20; d H-9 6.70; d 6.75; d 6.85; d H-10 7.05; d6.85; d 6.90; d diverse H 1.40-1.60 (m, 6H, 3 × —CH₂—*) 1.50-1.65 (m.6H, 3 × —CH₂—*) 4.35 (d. 2H, —N—CH₂—) 2.40 (m, 4H, 2 × —CH₂—N—*) 2.50(m, 2H, —CH₂—CH ₂—CH₂—) 5.70 (d, 2H, —CH═CH₂ ) 2.95 (m, 2H, —N—CH₂—CH₂—N—) 3.10-3.45 (m, 6H, 3 × —CH₂—N—*) 6.30 (m, 1H, —CH═CH₂) 4.35 (m, 2H,—N—CH₂ —CH₂—N—) 3.75 (t. 2H. —N—CH₂ —CH₂—CH₂—) *⁾Piperdin *⁾Piperidin

[0370] ¹³C-NMR [DMSO-d₆; δ (ppm)]: C-Atom  91    92  93 C-1  27.9; t 31.0; t    30.8  28.0; t C-5  29.6; t  32.1; t    31.9  30.6; t CH₃—N— 46.2; q  44.5; q    43.6  52.8; q C-4a  46.2; s  45.9; s    45.9  45.9;s C-6  60.1; t  51.6; t    49.2  50.2; t CH₃—O  55.7; q  55.6; q    55.6 66.0; q C-8  60.1; t  60.3; t    60.1  59.7; t C-2  60.8; d  59.5; d   59.5  59.7; d C-12a  88.0; d  86.5; d    86.6  86.8; d C-3 112.0; d121.1; d   112.0 111.8; d C-4 124.9; d 123.8; d   123.9 123.8; d C-9130.0; d 125.2; d   125.1 124.8; d C-10 132.3; d 130.1; d {circumflexover ( )}129.8 130.0; d C-8a 116.0; s 117.9; s   118.0 117.5; s C-11b132.3; s 132.7; s   132.6 132.5; s C-11a 146.0; s 145.4; s   145.4145.5; s C-11 146.1; s 146.4; s   146.3 146.2; s diverse C  13.5 (q,CH₃—)  27.5 (q, CH₃—N—)    23.1 (t, C-3* u. C-4*)  51.8 (t, —N—CH₂—CH₂—) 21.9 (t, CH₃—CH₂)  29.5 (q, CH₃—N—)    53.4 (t, C-2* u. C-5*)  55.4 (t,2 × —CH₂—N—*)  21.9 (t, CH₃—CH₂—CH₂—)  49.7 (t, —CH₂—N—)    65.0 (t,—CH₂—N—)  58.5 (t, —N—CH₂—CH₂—)  22.3 (t, —N—CH₂—CH₂—)  64.9 (t,—N—CH₂—)    65.9 (t, —N—CH₂—)  60.1 (t, 2 ×—O—CH₂—*)  60.1 (t,—N—CH₂—CH₂—) *) Pyrrolidine *⁾ Morpholine C-Atom  94  95 C-1  25.9; t 30.8; t C-5  30.0; t  40.0; t CH₃—N—  46.6; q  45.9; q C-4a  46.6; s 54.8; s C-6  53.8; t  55.6; t CH₃—O—  56.2; q  53.6; q C-8  60.8; t 59.6; t C-2  61.4; d  59.9; t C-12a  88.5; d  86.7; d C-3 112.4; d112.0; d C-4 123.4; d 123.9; d C-9 125.4; d 125.0; d C-10 129.8; d125.0; d C-8a 117.6; s 130.0; s C-11b 133.0; s 132.5; s C-11a 146.1; s145.4; s C-11 146.4; s 146.4; s diverse C  23.1 (t, C-4*)  19.3 (t,N—CH₂—CH₂—CH₂—N—)  23.9 (t, C-3* u. C-5*)  23.5 (t, C-4*)  24.7 (t,—N—CH₂—CH₂—N—)  25.0 (t, C-3* u. C-5*)  54.5 (t, C-2* u. C-6*)  53.6 (t,C-2* u. C-6*)  60.8 (t, —N—CH₂—CH₂—N—) *) Piperidin *) Piperidin

[0371] (+)-Alkyl Galanthamine Halogenide Empirical Product Formula NameR 96 C₂₃H₃₂ClN₂O₄ (−)-2-Morpholin-N-ethylgalanthaminium-chloride

97 C₂₅H₂₆ClN₂O₃ (−)-3-Piperidin-N-propylgalanthaminium-chloride

[0372] General Procedure

[0373] 800 mg (2.78 mmol) (−)-galanthamine and 3.84 g (27.8 mmol)potassium carbonate were presented in 100 mL acetone. After adding 1.5equivalents of halogenide and a spatula tip of potassium iodide, thereaction mixture was stilled under reflux for 24-36 hours. The potassiumcarbonate was then evaporated in a rotary evaporator and the filtratewas evaporated. The oily residue was finally cleaned by columnchromatography in a mixture of trichloromethane and ammoniacal methanol(9:1).

[0374] DC: CHCl₃: MeOH (10% NH₃)=9:1 Products Yield [% d. Th.] α_(D)(25°C., c = 1) Melting Point [° C.] 96 44 ÷48.6° 185-190 97 65 ÷64.0°118-124

[0375] N-Propargyl-galanthamine Bromide (99)

[0376] IR (KBr): 3439 s br; 3213 s; 3014 w; 2915 s br; 2133 w; 1619 s;1507 m; 1440 s; 1274 s; 1203 m; 1070 s; 1012 m; 951 m; 865 w; 791 s cm⁻¹

[0377]¹H-NMR (D₂O) δ: 6.95 (m, 2H; 6.12 (m, 2H); 5.08 (d, 1H); 4,70 (m,2H; 4.46 (m, 2H); 4.29 (m, 2H); 4.11 (m, 1H); 3.80 (s, 3H); 3.69 (m,1H); 3.00 (s, 3H); 2.41 (m, 2H); 2.20 (m, 2H).

[0378]¹³C-NMR (D₂O) δ: 148.1 (s); 147.9 (s); 134.5 (s); 130.2 (d); 127.7(d); 127.0 (d); 119.4 (q); 114.7 (d); 89.6 (d); 85.0 (d); 72.6 (s); 67.5(t); 63.3 (t); 62.4 (d); 61.0 (t); 58.1 (q); 48.1 (s); 46.3 (q); 33.5(t); 31.3 (t).

[0379] N-Acetamido-galanthamine Bromide (100)

[0380]¹H-NMR (D₂O) δ: 6.95 (m, 2H); 6.13 (m, 2H); 5.18 (d, 1H);4.70-4.28 (m, 7H; 3.83 (s, 3H); 3.08 (s, 3H); 2.50 (d, 1H); 2.39 (d,1H); 2.18 (m, 2H).

[0381]¹³C-NMR D₂O) δ: 168.7 (s); 148.2 (s); 148.0 (s); 134.7 (s); 130.2(d); 128.2 (d); 127.2 (d); 119.5 (s); 114.8 (d); 89.7 (d); 68.3 (t);64.0 (t); 62.5 (d); 59.6 (t); 58.2 (q); 48.2 (q); 33.5 (t); 31.3 (t);18.9 (q).

[0382] (−)-Galanthamine-N-oxide (98):

[0383] 1.5 g (4.08 mmol) (−)-galanthamine hydrobromide are dissolved in50 mL water, precipitated with concentrated aqueous ammonia andextracted with three times 25 mL trichloromethane. The organic phase iscompressed to 30 to 50 mL and treated with 1.4 g (4.08 mmol) 50%metachloroperbenzoic acid. After 30 minutes, the reaction mixture isevaporated and placed on a pan column. The major part of the theoreticalyield metachloroperbenzoic acid is then separated with trichloromethane,and the N-oxide is then washed out with trichloromethane:methanol=1:1.The further cleaning of the theoretical yield N-oxide is effected bymeans of MPLC (60 g SiO₂, LM: CHCl₃: MeOH=2:1), whereby quantitativelycolorless crystals with a melting point of 80-85° C. and a rotation ofa_(D) ²⁶[MeOH]=−102.9° at 98.

[0384] DC: CHCl₃: MeOH=8:2

[0385]¹H-NMR (DMSO-d₆; δ (ppm)): 1.75-1.95 (m, 1H, H-9); 2.00-2.40 (m,3H, H-5/5′/9′); 2.95 (s, 3H, NCH₃); 3.30-3.75 (m, 2H, H-10/10′); 3.75(s, 3H, OCH₃); 4.10 (b, 1H, H-12); 4.35 (d, 1H, H-12′); 4.60 (b, 1H,H-6); 4.95 (breites d, 1H, H-4a); 5.90 (dd, 1H, H-8); 6.15 (b, 1H, H-7);6.75-6.90 (m, 2H, H-1/2)

[0386]¹³C-NMR (DMSO-d₆; δ (ppm)): 31.2 (t, C-5); 34.3 (t, C-9); 45.6 (s,C-8a); 52.5 (q, NCH₃); 55.5 (q, OCH₃); 59.5 (d, C-6); 69.0 (t, C-10);73.9 (t, C-12); 86.6 (d, C4a); 112.0 (d, C-8); 120.0 (s, C-12a); 122.9(d, C-7); 125.1 (d, C-2); 130.3 (d, C-1), 132.0 (s, C-12b); 144.9 (s,C-3a); 146.5 (s, C-3)

[0387](6R)-4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-methyl-12-oxo-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol(102)

[0388] A suspension of 450 mg (1.19 mmol)4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-methyl-12-oxo-6H-benzofuro[3a,3,2-e]f[2]benza-zepin-6-on(101) in 10 mL absolute tetrahydrofuran is treated at 0° C. with 3.6 mL(3.6 mmol) 1 N L-Selectride solution in tetrahydrofuran. After 30minutes, it is hydrolyzed with 5 mL water:tetrahydrofuran 1:1. Thereaction mixture is then evaporated, the residue is absorbed in 80 mL 2Nhydrochloric acid and stilled for 1 hour at room temperature.Subsequently, it is extracted three times with 40 mL each of ethylacetate. The combined organic phases are washed once with saturatedaqueous sodium chloride solution, dried (Na₂SO₄), filtered and condensedby evaporation, whereby a quantitative crude product is obtained, whichis cleaned by column chromatography (15 g silica gel, flow agent: CHCl₃:MeOH=9:1), whereby quantitative colorless crystals are obtained with amelting point of 188-189° C. at 102.

[0389] DC: CHCl₃: MeOH=8:2

[0390]¹H-NMR (CDCl₃; δ (ppm)): 1.73 (ddd, 1H, H-9, J_((9,9′))=15.1 Hz);2.03 (ddd, 1H, H-9′, J_((9,9′))=15.1 Hz); 2.27 (ddd, 1H, H-5,J_((5,5′))=14.3 Hz); 2.64 (ddd, 1H, H-5′, J_((5,5′))=14.3 Hz); 3.18 (s,3H, NCH₃); 3.19 (ddd, 1H, H-10, J_((10,10′))=14.8 Hz); 3.75 (ddd, 1H,H-10′, J_((10,10′))=14.8 Hz); 3.86 (s, 3H, OCH₃); 4.10 (b, 1H, H-6);4.69 (b, 1H, H-4a); 5.48 (d, 1H, H-8, J_((7,8))=10.0 Hz); 5.88 (dd, 1H,H-7, J_((7,8))=10.0 Hz); 7.10 (s, 1H, H-2)

[0391]¹³C-NMR (CDCl₃; δ (ppm)): 29.8 (t, C-5); 34.1 (q, NCH₃); 38.2 (t,C-9); 48.3 (s, C-8a); 48.8 (t, C-10); 56.3 (q, OCH₃); 60.9 (d, C-6);89.9 (d, C-4a); 113.8 (s, C-1); 118.0 (d, C-8); 123.3 (s, C-12a); 126.3(d, C-7); 130.8 (d, C-2); 132.1 (s, C-12b); 144.8 (s, C-3); 146.2 (s,C-3a); 165.1 (s, C-12)

[0392] Manufacture of Products 105, 107

[0393] Method: A mixture of 500 mg (1.42 mmol)N-demethyl-bromo-galanthamine (4), 391 mg (2.84 mmol) potassiumcarbonate arid 272 mg (1.70 mmol) potassium iodide is thoroughly groundin a mortar. The mixture is then treated in 20 mL absolute acetone with1.2 equivalents of halogenide reagent and heated to reflux. Aftercomplete conversion (DC), the reaction mixture is condensed byevaporation, the residue is absorbed in 100 mL 2 N hydrochloric acid,washed with ethyl acetate, made basic with concentrated aqueous ammoniaand the precipitate is their evaporated in a rotary evaporator orextracted three times with 30 mL each of ethyl acetate. The precipitateis dried at 50° C./50 mbar, the combined organic phases are washed oncewith saturated aqueous sodium chloride solution, dried (Na₂SO₄, activecarbon), filtered fluid evaporated. Additional cleaning is effected bycolumn chromatography (15 g silica gel, flow agent: CHCl₃>>>CHCl₃:MeOH=9:1). DC: CHCl₃: MeOH=8:2

[0394] 105:

[0395] Educt: (4) and (136). Yield: 62.3% of the theoretical yield,colorless foam.

[0396]¹H-NMR (CDCl₃; δ (ppm)): 2.36-1.36 (m, 12 H); 2.62 (ddd, 1H);2.89-3.35 (m, 7H); 3.60 (2H, m), 3.80 (s, 3H); 3.85 (d, 1H); 4.10 (dd,1H); 4.29 (H, b), 4.48 (d, 1H); 4.56 (b, 1H), 5.90-6.05 (m, 2H:);6.85-6.69 (4H, m), 7.23 (2H, m)

[0397] 107:

[0398] Educt: (4) and (137). Yield: 44.9% of the theoretical yield,colorless foam.

[0399]¹H-NMR (CDCl₃; δ (ppm)): 1.65-1.85 (4H, m), 2.20-1.90 (m, 6 H);2.60-2.28 (2H, m) 2.62 (ddd, 1H); 2.89-3.35 (m, 5H); 3.60 (2H, m), 3.80(s, 3H); 3.85 (d, 1H; 4.10 (dd, 1H); 4.20 (H, b), 4.48 (d, 1H); 4.56 (b,1H), 5.90-6.05 (m, 2H); 6.65-6.30 (4H, m), 7.05-6.83 (2H, m)

[0400] Procedure for Product 109:

[0401] 1.25 g (139) are heated to reflux temperature in 10 mL thionylchloride, the excess thionyl chloride is distilled off, the residue isabsorbed in 40 mL water-free THF arid added dropwise to a solution of2.0 g (4) in 20 mL THF and stirred for 1 hour at reflux temperature. Thereaction mixture is evaporated and the crude product is purified bycolumn chromatography (CHCl₃/MeOH, 2-5%): 1.75 g (57% of the theoreticalyield.) colorless foam (109).

[0402]¹H-NMR (CDCl₃; δ (ppm)): 1.65-1.85 (m, 4H), 1.98 (ddd, 1H); 2.25(b, 2H); 2.67-2.58 (m, 3H); 2.75-2.71 (2H, m), 2.87 (H, dd), 3.05-3.35(m, 5H); 3.55 (2H, m), 3.67-3.74 (2H, d), 3.80 (s, 3H); 3.85 (d, 1H);4.10 (dd, 1H); 4.40 (d, 1H); 4.56 (b, 1H); 5.90-6.05 (m, 2H); 6.85 (s,H), 7.30 (5H, m)

[0403] Procedure for Product 108:

[0404] 1.0 g (144) are heated for 2 hours to reflux temperature in 10 mLthionyl chloride, the excess thionyl chloride is distilled off, theresidue is absorbed in 20 mL water-free THF and added dropwise to asolution of 1.33 g (4) in 20 mL THF and stirred for 1 hour at roomtemperature. The reaction mixture is evaporated, absorbed in a NaHCO₃solution and extracted with ether (3×40 mL). The ether phase isevaporated and the crude product is purified by column chromatography(CHCl₃/MeOH, 5%): 1.22 g (56% of the theoretical yield.) colorless foam(108).

[0405]¹H-NMR (CDCl₃; δ (ppm)): 1.63-1.80 (m, 4H), 1.98 (ddd, 1H); 2.20(b, 2H); 2.61-2.48 (m, 3H); 2.69-2.74 (2H, m), 2.90 (H, dd), 3.02-3.45(m, 3H); 3.59 (2H, m), 3.60-3.72 (2H, d), 3.87 (s, 3H); 3.95 (d, 1H);4.22 (dd, 1H); 4.45 (d, 1H); 4.76 (b, 1H); 5.68-6.00 (m, 2H); 6.95 (s,1H), 7.10-7.42 (5H, m)

[0406] “Maritidinon-Type” 4,4a-dihydro-7-bromo-9-methoxy-3-oxo (3H,6H)(5,10b) ethanophenanthridine-10-ol (113)

[0407] A solution of 4.70 g (13.4 mmol) N-demethyl-bromonarwedine (15)and 2.35 g calcium chloride are heated to reflux for 3.5 hours in 200 mL70% ethanol. The reaction mixture is subsequently rotated, the residueis absorbed in 80 mL 1 N hydrochloric acid and the product isprecipitated with concentrated aqueous ammonia. After overnight cooling(+4° C.) the precipitate is sucked off and dried at 50° C./ 50 mbar. Theaqueous phase is extracted three times with ethyl acetate, the combinedorganic phases are washed once with a saturated aqueous sodium chloridesolution, dried (Na₂SO₄), filtered and evaporated, whereby 4.37 g (93%of the theoretical yield.) colorless crystals of 113 with a meltingpoint of 185-190° C. are obtained.

[0408] DC: EtOAc: MeOH=8:2

[0409]¹H-NMR (DMSO-d₆; δ (ppm)): 1.95 (ddd, 1H, H-11); 2.15 (ddd, 1H,H-11′); 2.30 (dd, 1H, H-4, J_((4,4′))=16.0 Hz); 2.65 (dd, 1H, H-4′,J_((4,4′))=16.0 Hz); 2.80 (ddd, 1H, H-12, J_((17,12′))=15.1 Hz); 3.05(ddd, 1H, H-12′, J_((1,12′))=15.1 Hz); 3.30 (dd, 1H, H-4a); 3.55 (d, 1H,H-6, J_((6,6′))=16.9 Hz); 3.75 (s, 3H, O—CH₃); 3.90 (d, 1H, H-6′,J_((6,6′))=16.9 Hz); 5.80 (d, 1H, H-2, J_((1,2))=9.3 Hz); 7.00 (s, 1H,H-8); 7.90 (d, 1H, H-1, J_((1,2))=9.3 Hz)

[0410]¹³C-NMR (DMSO-d₆; δ (ppm)): 38.0 (t, C-11); 39.8 (t, C4); 42.8 (s,C-10b); 53.1 (t, C-12); 55.9 (t, C-6); 56.0 (q, OCH₃); 64.1 (d, C-4a);109.6 (s, C-7); 113.6 (d, C-2); 123.2 (s, C-6a); 126.6 (d, C-8); 129.1(s, C-10a); 142.9 (s, C-10); 147.5 (s, C-9); 155.3 (d, C-1); 197.4 (s,C-3)

[0411] 35-4,4a-dihydro-7-bromo-9-methoxy-10-hydroxy (3H,6H) (5,10b)ethanophenanthridine-3-ol (114):

[0412] To a solution of 1.0 g (2.86 mmol) maritidinon-type (113) in 5 mLabsolute tetrahydrofuran, 10 mL of a 1 N L-Selectrid-solution intetrahydrofuran are added dropwise at 0° C.; it is then quickly heatedto reflux. After 1.5 hours, hydrolyze at 0° C. with 10 mLtetrahydrofuran:water 1:1 and the tetrahydrofuran is spun off. Theresidue is absorbed in 80 mL 1 N hydrochloric acid, made basic withconcentrated aqueous ammonia and extracted with ethyl acetate. Thecombined organic phases are washed with a saturated aqueous sodiumchloride solution, dried (Na₂SO₄), filtered and evaporated, wherebyquantitative yellow crystals of 114 with a melting point of 165-167° C.are obtained. DC: CHCl₃ : MeOH=9:1.

[0413] 114 and 3R-2,3,4,4a-tetrahydro-7-bromo-9-methoxy-10-hydroxy(1H,6H) (5,10b) ethanophenanthridine-10-ol (116):

[0414] To a solution of 1.0 g (0.29 mmol) maritidinon-type (113) in 1 mLabsolute tetrahydrofuran, 1 mL of a 1 N L-Selectrid-solution intetrahydrofuran is added dropwise and agitated at 0° C. After 1 hour, anadditional 1 mL a 1 N L-Selectrid-solution in tetrahydrofuran is addeddropwise and agitated for 2.5 hours at 0° C. and for 3.5 hours at roomtemperature. It is subsequently hydrolyzed with 2 mL of a 1:1 mixture oftetrahydrofuran and water, made basic with concentrated aqueous ammoniaafter brief agitation and extracted with ethyl acetate. The combinedorganic phases are washed with a saturated aqueous sodium chloridesolution, dried (Na₂SO₄), filtered and evaporated. The two products areseparated by column chromatography (7 g silica gel, flow agent: CHCl₃:MeOH=8:2), yielding 30 mg (30% of the theoretical yield) colorlesscrystals of 114 and 20 mg (20% of die theoretical yield) of colorlesscrystals of 116.

[0415] DC: CHCl₃: MeOH=9:1

[0416] 114:

[0417]¹H-NMR (CDCl₃; δ ppm)): 1.50 (ddd, 1H, H-4); 1.80 (ddd, 1H, H-11);2.20 (ddd, 1H, H-11′); 2.45 (ddd, 1H, H-4′), 2.60-2.80 (n, 2H, H-4a/12);3.30 (ddd, 1H, H-12′); 3.60 (d, 1H, H-6,J_((6,6′))=17.8 Hz); 3.75 (s,3H, OCH₃); 4.00 (d, 1H H-6′, J_((6,6′))=17.8 Hz); 4.30 (dd, 1H, H-3);5.55 (dd, 1H H-2, J_((2,3))=9.8 Hz); 6.75 (dd, 1H, H-3, J_((2,3))=9.8Hz); 6.80 (s, 1H, H-8)

[0418]¹³C-NMR (CDCl₃; δ ppm)): 26.9 (t, C-11); 35.7 (t, C-4); 37.7 (s,C-10b); 47.7 (t, C-12); 50.7 (t, C-6); 51.0 (q, OCH₃); 58.8 (d, C-4a);62.8 (d, C-3); 105.3 (s, C-7); 107.4 (d, C-2); 118.3 (s, C-6a); 124.8(d, C-8); 125.5 (s, C-10a); 127.4 (d, C-1); 137.9 (s, C-10); 141.3 (s,C-9)

[0419] 116:

[0420]¹H-NMR (CDCl₃; δ ppm)): 1.55-1.95 (m, 4H, H-1/1′/4/11); 2.15 (m,1H, H-11′); 2.35 (m, 1H, H-2); 2.60 (dd, 1H, H-4′); 2.75-2.95 (m, 2H,H-4a/12); 3.15 (dd, 1H, H-2′); 3.40 (ddd, 1H, H-12′); 3.70 (d, 1H, H-6,J_((6,6′))=6.2 Hz); 3.85 (d, 3H, OCH₃); 4.00 (d, 1H, H-6′,J_((6,6′))=6.2 Hz); 4.15 (ddd, 1H H-3); 6.90 (s, 1H, H-8)

[0421] 35-4,4a-dihydro-9-methoxy-10-hydroxy (3H,6H) (5,10b)ethanophenanthridine-3-ol (115):

[0422] A solution of 1.0 g (2.84 mmol) maritidinon-type (114) and 2.0 gcalcium chloride are treated in 50 mL 50% ethanol with 4.0 g freshlyactivated zinc powder and heated to reflux for 2 hours. Subsequently,the excess zinc is filtered off, washed with methanol and the residualsolution is spun off. The residue is absorbed in 80 mL 1 N hydrochloricacid, made basic with concentrated aqueous ammonia and extracted withthree times ethyl acetate. The combined organic phases are washed with asaturated aqueous sodium chloride solution, dried (Na₂SO₄, activecarbon), filtered and evaporated, yielding 450 mg crude product which iscleaned by column chromatography (7 g silica gel, flow agent initiallyCHCl₃ : MeOH=8:2, then CHCl₃ : MeOH : NH₄OH=49.9 : 49.9 : 0.2), fromwhich 270 mg (35% of the theoretical yield) red crystals of 115 areobtained, with a melting point of 59-60° C. are obtained.

[0423] DC: CHCl₃: MeOH=9:1

[0424]¹H-NMR (DMSO-d₆; δ (ppm)): 1.40 (ddd, 1H, H-4); 1.65 (ddd, 1H,H-11); 2.00 (ddd, 1H, H-11′); 2.20 (ddd, 1H, H-4′); 2.65 (dd, 1H H-4a);3.10 (ddd, 1H, H-12); 3.30-3.50 (m, 1H, H-12′); 3.45 (d, 1H, H-6,J_((6,6′))=15.1 Hz); 3.75 (s, 3H, OCH₃); 4.05 (d, 1H, H-6′,J_((6,6′))=15.1 Hz); 4.20 (dd, 1H, H-3); 5.45 (d, 1H, H-2, J_((1,2))=8.9Hz); 6.40 (d, 1H, H-1, J_((1,2))=8.9 Hz); 6.65-6.75 (m, 2H, H-7/8); 8.40(b, 1H tauscht D₂O, Ph—OH)

[0425]¹³C-NMR (DMSO-d₆; δ (ppm)): 32.2 (t, C-11); 41.1 (t, C-4); 42.7(s, C-10b); 52.3 (t, C-12); 54.6 (t, C-6); 55.8 (q, OCH₃); 64.1 (d,C-4a); 67.1 (d, C-3); 109.4 (d, C-7); 115.8 (d, C-2); 124.9 (s, C-6a);129.9 (s, C-10a); 130.2 (d, C-8); 132.5 (d, C-1); 143.7 (s, C-10); 146.0(s, C-9)

[0426] [4aS-(4aa, 6β,8aR*)]-4a,5,9,10,11,12-hexahydro=3-methoxy-11-methoxy-11-nitro-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol(117):

[0427] To a solution of 250 mg (0.87 mmol) galanthamine in 10 mL glacialacetic acid, a mixture of 0.5 mL smoking nitric acid and 2 mL glacialacetic acid is added dropwise at 15-20° C. After one hour of agitationat room temperature, additional 0.25 mL smoking nitric acid in 1 mLglacial acetic acid is added dropwise and agitated for 1 additionalhour. Subsequently, it is poured on 80 mL water and made basic with a40% sodium hydroxide solution. The aqueous phase is extracted threetimes with 30 mL each of ethyl acetate. The combined organic phases arewashed once with saturated aqueous sodium chloride solution, dried(Na₂SO₄), filtered and evaporated, yielding 252 mg (87% of thetheoretical yield.) yellow crystals of 117 witl a melting point of48-50° C.

[0428] DC: CHCl : MeOH=9:1

[0429]¹H-NMR (CDCl₃; δ (ppm)): 1.67 (ddd, 1H, H-9); 1.95-2.30 (m, 2H,H-5/9′); 2.20 (ddd, 1H, H-5′); 2.44 (s, 3H, NCH₃); 2.91 (ddd, 1H, H-10);3.18 (ddd, 1H, H-10′); 3.87 (s, 3H, OCH₃); 4.01 (d, 1H, H-12); 4.16 (dd,1H, H-6); 4.32 (d, 1H, H-12′); 4.68 (b, 1H, H-4a); 6.04 (dd, 1H, H-8);6.16 (d, 1H, H-7); 7.35 (s, 1H, H-2)

[0430]¹³C-NMR (CDCl₃; δ (ppm)): 29.6 (t, C-5); 33.3 (t, C-9); 43.6 (q,NCH₃); 48.5 (s, C-8a); 53.4 (t, C-10); 54.4 (t, C-12); 56.1 (q, OCH₃);61.4 (d, C-6); 89.6 (s, C-4a); 108.9 (d, C-8); 126.5 (,); 126.9 (,);128.3 (d, C-7); 134.8 (,); 143.0 (,); 143.4 (,); 149.8 (,)

[0431] [4aS-(4aa, 6β,8aR*)]-4a.5,9,10,11,12-Hexahydro-1-amino-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol(118):

[0432] To a solution of 200 mg (0.60 mmol) 117 in 10 mL methanol asolution of 420 mg (2.4 mmol) sodium dithionite in 10 mL water is addeddropwise at room temperature and agitated for 1 hour. The methanol issubsequently spun out, the residue is absorbed in 50 mL water, madebasic with concentrated aqueous ammonia and extracted five times with 30mL each of trichloromethane. The combined organic phases are washed oncewith saturated aqueous sodium chloride solution, dried (Na₂SO₄),filtered and evaporated, yielding 148 mg (82% of the theoretical yield.)yellow crystals of 118 with a melting point of 151-153° C.

[0433] DC: CHCl₃: MeOH=9:1

[0434]¹H-NMR (CDCl₃, δ (ppm)): 1.59 (ddd, 1H, H-9); 1.90-2.10 (m, 2H,H-5/9′); 2.43 (s, 3H, NCH₃); 2.62 (ddd, 1H, H-5′); 2.96 (ddd, 1H, H-10);3.20 (ddd, 1H, H-10′); 3.70 (d, 1H, H-12); 3.79 (s, 3H, OCH₃); 4.10 (d,1H, H-12′); 4.52 (b, 1H, H-4a); 5.98 (dd, 1H, H-8); 6.08 (d, 1H, H-7);6.16 (s, 1H, H-2)

[0435] New, substituted, bridged-over bases:

Substance No. J-No. R₂₃ R₂₃ 120 Benzyl p-Nitro-phenyl- 121 Benzylp-Amino-phenyl 122 Benzyl p-Chlorphenyl 123 Benzyl p-Hydroxyphenyl 124Benzyl o-Nitrophenyl 125 Benzyl o-Aminophenyl 126 Benzyl o-Chlorphenyl127 Benzyl o-Dimethylaminophenyl 128 p-Ts Phenyl 129 H Phenyl 130 p-Tsp-Methylphenyl 131 H p-Methylphenyl 132 p-Ts p-Chlorphenyl 133 Hp-Chlorphenyl 134 p-Ts p-Fluorphenyl 135 H p-Fluorphenyl 136—CH₂—CH₂—CH₂—Cl Phenyl 137 —CH₂—CH₂—Cl p-Fluorphenyl 138 —CH₂—CH₂—OHt-BOC 139 —CH₂—CH₂—OH Benzyl 140 —CH₂—CN Benzyl 141 —CH₂—CH₂—NH₂ Benzyl142 —CH₂—CH₂—CN Benzyl 143 —(CH₂)₃—NH₂ Benzyl 144 —CH₂—COOEt Benzyl 145t-BOC —CH(Ph)₂

[0436] 5-Benzyl-2-(4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane (120)

[0437] To a solution of 5.30 g 2-benzyl-2,5-diazabicyclo[2.2.1]heptane×2HBr in 20 mL anhydrous DMSO, 3.97 dried, fine ground K₂CO₃ and 2.03 g4-nitrobenzene fluoride were added. It was then agitated magnetically at80° C. for 3 hours, poured on 100 mL water, the precipitated crystalswere sucked off, washed with diisopropyl ether and dried in vacuum: 4.10g (120) as colorless crystals (92% of the theoretical yield.), meltingpoint 170-173° C. DC: toluene/acetone (1:1) or CHCl₃.

[0438]¹H-NMR (CDCl₃): 8.10 (2H, d), 7.35−7.2 (51H, m), 6.45 (2H, d),4.40 (1H, m), 3.75 (2H, s), 3.65 (1H, b), 3.45(2H, dd), 2.95, 2.30(2R,dd), 2.10, 1.85(2H, dd)

[0439]¹³C-NMR (CDCl₃): 151.14, 139.01, 136.55, 128.26, 126.97, 126.35,110.42, 60.42, 58.28, 58.191, 53.17, 35.78.

[0440] 5-Benzyl-2-(4-aminophenyl)-2,5-diazabicyclo[2.2.1]heptane (121)

[0441] 4.1 g (120) in 360 mL ethanol and 20 mL water with 5 g NH₄Cl and7 iron powder were heated to reflux temperature under 4 hours ofmechanical agitation. The reaction solution is filtered over Celite andactive carbon, evaporated, absorbed in 100 mL water, brought to pH 10with K₂CO₃ and extracted with ether (4×50 mL). The combined organicphases were dried with Na₂SO₄, evaporated and distilled in a bulb tube(Kp: 5 mBar; 160-170° C.): 3.0 g (81% of the theoretical yield.) (121)as colorless oil.

[0442] DC: CHCl₃/methanol (9:1).

[0443]¹H-NM (CDCl₃): 7.35−7.15 (5H, m), 6.65 (2H, d), 6.45 (2H, d), 4.15(1H, m), 3.70 (2H, s), 3.50 (H, m) 3.40, 3.30 (2H, dd), 3.20 (2H, b),2.90, 2.70 (2H, dd), 2.05−1.85 (2H, dd)

[0444] 5-Benzyl-2-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]heptane (122)

[0445] 1.5 g (121) were dissolved in 20 mL concentrated HCl and addeddropwise at 0-5° C. to a solution of 0.38 g NaNO₂ in 3 mL water, so thatthe temperature remained under 5° C. The solution was the added dropwiseto a solution produced from 1.61 g CuSO₃×5 H₂O, 0.41 g NaCl, 0.39 gNaHSO₃ and 0.23 g NaOH and CuCl in 10 mL HCl and heated for 4 hours to50° C. It was then poured on 100 mL water, made alkaline with K₂CO₃ andextracted with ether (5×100 mL). Concentration by evaporation and bulbtube distillation (Kp: 5 mbar; 135° C.) yielded 0.6 g(37% of thetheoretical yield.) (122) as a colorless oil.

[0446] DC: CHCl₃/methanol (9:1).

[0447]¹H-NMR (CDCl₃): 7.40−7.15 (7H, m), 6.90−6.50 (2H, m), 4.25 (1H,m), 3.70 (2H, s), 3.60−3.45 (H, m), 3.45−3.30 (2H, m), 2.95, 2.70 (2H,dd), 2.10−1.80 (2H, m).

[0448] 5-Benzyl-2-(4-hydroxyphenyl)-2,5-diazabicyclo[2.2.1]heptane (123)

[0449] To a solution of 1.17 g (122) in 17 mL concentrated HCl: 0.35 gNaNO₂ in 5 mL water were added slowly dropwise, so that the temperatureremained below 5° C. The solution was agitated for 2 hours at 60° C.,neutralized with NaHSO₃ and extracted with ether (4×50 mL). The combinedorganic phases were dried with Na₂SO₄, evaporated and distilled in abulb tube (Kp: 0.05 mbar; 140° C.): 0.1 g (123) (123) as colorless oil.DC: CHCl₃/methanol (9:1).

[0450]¹H-NMR (CDCl₃): 7.50−7.00 (8H, m), 6.85−6.40 (2H, m), 4.25 (1, m),3.80−3.30 (5H, m), 3.05−2.65 (2H, m), 2.05, 1.90 (2H, dd).

[0451] 5-Benzyl-2-(2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane (124)

[0452] To a solution of 22.3 g 2-benzyl-2,5-diazabicyclo[2.2.1]heptane×2HBr in 110 mL anhydrous DMSO, 17.6 g dried, finely ground K₂CO₃ and 9.0g 2-nitrobenzene fluoride were added. It was then agitated magneticallyat 80° C. for 3 hours, poured on 300 mL water, the precipitated crystalswere sucked off, washed with diisopropyl ether and dried in vacuum: 19.1g (124) as colorless crystals (96.9% of the theoretical yield.), meltingpoint 107-108° C.

[0453] DC: toulene/acetone (1:1) or CHCl₃.

[0454]¹H-NMR (CDCl₃): 7.75 (H, d), 7.35 (H, d), 7.30−7.15 (5H, m),6.85−6.70 (2H, m), 4.30 (H, m), 3.65 (2H, s), 3.55 (2H, m), 2.90 (2H,dd), 2.85 (H, m), 2.00 (2H, dd).

[0455] 5-Benzyl-2-(2-aminophenyl)-2,5-diazabicyclo[2.2.1]heptane (125)

[0456] 5.0 g (124) in 360 mL ethanol and 20 mL water with 4 g NH₄Cl and6.7 iron powder were heated to reflux temperature under 4 hours ofmechanical agitation. The reaction solution is filtered over Celite andactive carbon, evaporated, absorbed in 100 mL water, brought to pH 10 bymeans of K₂CO₃ and extracted with ether (4×50 mL). The combined organicphases were dried with Na₂SO₄, evaporated and distilled in a bulb tube(Kp: 5 mbar; 160-170° C.): 2.20 g (48.8% of the theoretical yield.)(125) as colorless oil. DC: CHCl₃/methanol (9:1).

[0457]¹H-NMR (CDCl₃): 7.45−7.20 (5H, m), 7.05−6.65 (4H, m), 3.95−3.65(5H, m), 3.60−3.40 (2H, m), 3.20−3.00 (H, m), 2.95−2.75 (2H, m),2.00−1.85 (2H, m).

[0458] 5-Benzyl-2-(2-chlorophenyl)-2,5-diazabicyclo[2.2.1]heptane (126)

[0459] Procedure analogous to (122).

[0460] Yield after bulb tube distillation (Kp: 5 mbar, 135° C.): 0.60 g(37.5% of the theoretical yield.) (126) as colorless oil. DC:CHCl₃/Methanol (9:1).

[0461]¹H-NMR (CDCl₃): 7.50−7.20 (6H, m), 6.85−6.55 (3H, m), 4.25 (H, m),3.85−3.70 (2H, s), 3.65−3.50 (H, b), 3.45−3.30 (2H, m), 3.00, 2.75 (2H,dd), 2.15−1.80 (2H, m)

[0462] 5-Benzyl-2-(2-dimethylaminophenyl)-2,5-diazabicyclo[2.2.1]heptane(127)

[0463] 5-Benzyl-2-(2-methylaminophenyl)-2,5-diazabicyclo[2.2.1]heptane(127a)

[0464] 0.95 g (125) with 0.5 g PO(OMe)₃ were heated for 3 hours to160-180° C., cooled, hydrolyzed with 5 mL 30% NaOH, 10 mL water wereadded, and them extracted with ether (3×10 mL). Concentration byevaporation and color chromatography (CHCl₃/Methanol 3%) yielded 0.15 gcolorless oil (127-a) (15.6% of the theoretical yield.) and 0.09 gcolorless oil (107) (8.5% of the theoretical yield.).

[0465]¹H-NMR (CDCl₃) (127-b): 7.45−7.20 (5H, m), 7.10−6.95 (2H, t),6.80−6.00 (2H, dd), 3.90−3.65 (4H, m), 3.65−3.40 (2H, dd), 3.50−2.60(6H, m), 2.0−1.80 (2H, m)

[0466]¹H-NMR (CDCl₃) (127): 7.40−7.20 (5H, m), 6.70−6.55 (3H, m), 6.40(H, m), 3.75 (2H, s) −3.30−3.65 (H, m), 3.60−3.55 (2H, dd), 3.45−3.20(3H, m), 2.90−2.75 (6H, s,s), 2.30−2.15 (2H, dd).

[0467] Production of phenyl-substituted 2.5-diazabicyclo[2.2.1]heptane:Melting Point/ No. Yield Kp DC Method 128 62.5%   139-143° C.Petrolether/EtOAc (7:3) A 129 71% 0.05 mbar/ DC: CHCl₃/Methanol (9:1) B120-130°     130 46% 149-151° C. DC: Petrolether/EtOAc (7:3) A 131 65%0.05 mbar/ DC: CHCl₃/Methanol (9:1) B 130-140° C. 132 69% 214-217° C.DC: Petrolether/EtOAc (7:3) A 133 56% 0.05 mbar/ DC: CHCl₃/Methanol(9:1) B 120-130° C. 134 55% Melting DC: Petrolether/EtOAc (7:3) A Point:180-184° C. 135 74% 0.05 mbar/ DC: CHCl₃/Methanol (9:1) B 120-130° C.

[0468] Method (A) for Cyclization of tritosyl-4-hydroxyprolinol:

[0469] 20 g (35 mmol) tritosyl-4-hydroxyprolinol with 75 mL toluene, 9.8g (100 mmol) triethylamine and 35 mmol of the theoretical yieldeappropriately substituted aniline (freshly distilled or uncrystallized)are heated in a steel autoclave for 3 hours to 160-170° C. After coolingand opening of the theoretical yielde autoclave, the product is rinsedout from the autoclave with 100 mL toluene, shaken once with 100 m; NaClsolution and once with 100 NaHCO₃, and the organic phase is dried bymeans of Na₂SO₄ and evaporated. The crystalline product is digested withisopropyl, filtered and dried.

[0470] Method (B) for Splitting Off the p-Ts Protective Group

[0471] 2.5 g educt in 40 mL glacial acetic acid and 20 mL concentratedsulfuric acid are agitated for 2 hours at 80° C. Subsequently, it ispoured on 200 mL ice/water, extracted with EtOAc (2 times 100 mL) (EtOAcphase is discarded), the aqueous phase is treated with 30% NaOH to ph 12and extracted with EtOAc (6×50 mL). The Ethyl acetate phase isevaporated and bulb-tube distilled: colorless oil.

[0472] NMR Spectra:

[0473] 5-Phenyl-2-p-tosyl-2,5-diazabicyclo[2.2.1]heptane (128)

[0474]¹H-NMR (CDCl₃): 7.68 (2H, d), 7.29 (2H, d), 7.18 (2H, m), 6.72 (H,t), 6.4 (2H, dd), 4.51 (H, b), 4.32 (H, b), 3.52 (2H, dd), 3.24 (2H,dd), 2.42 (3H, s), 1.86 (H, d), 1.40 (H, d).

[0475]¹³C-NMR (CDCl₃): 146.18, 143.49, 135.27, 129.66, 129.10, 127.18,116.84, 112.39, 59.98, 56.91, 56.52, 52.25, 36.50, 21.37.

[0476] 2-Phenyl-2,5-diazabicyclo[2.2.1]heptane (129)

[0477]¹H-NMR (CDCl₃): 7.23 (2H, m), 6.71 (3H, m), 4.30 (H, b), 3.78 (H,b), 3.66 (H, dd), 3.18−2.89 (3H, m), 2.06−1.78 (3H, m).

[0478]¹³C-NMR (CDCl₃): 146.92, 129.09, 116.08, 112.41, 59.78, 56.62,56.22, 49.65, 37.18

[0479] 5-(4-Methylphenyl)-2-p-tosyl-2,5-diazabicyclo[2.2.1]heptane (130)

[0480]¹H-NMR (CDCl₃): 7.68 (2H, d), 7.27 (2H, d), 7.00 (2H, d), 6.36(2H, d), 4.49 (H, s) 4.25 (H, s), 3.53 (H, d), 3.46 (H, dd), 3.26 (H,dd), 3.17 (H, d), 2.41 (3H, s), 2.24 (3H, s), 1.83 (H, d), 1.38 (H, d).

[0481]¹³C-NMR (CDCl₃): 144.09, 143.44, 135,35, 129.63, 127.30, 125.96,112.55, 60.02, 57.06, 56.73, 51.99, 36.46, 21.36, 20.16.

[0482] 2-(4-Methylphenyl)-2,5-diazabicyclo[2.2.1]heptane (131)

[0483]¹H-NMR (CDCl₃): 7.05 (2H, d), 6.48 (2H, d), 4.25 (H, s), 3.77 (H,s), 3.68 (H,dd), 3.16 (H, dd) 3.02 (1H, dd), 2.92 (H, dd), 2.24 (3H, s),1.95 (H, d), 1.82 (H, b), 1.80, (H,d).

[0484] 5-(4-Chlorophenyl)-2-p-tosyl-2,5-diazabicyclo[2.2.1]heptane (132)

[0485]¹H-NMR (CDCl₃): 7.52 (2H, d), 7.13 (2H, d), 6.96 (2H, d), 6.22(2H, d), 4.38 (H, s), 4.12 (H, s), 3.40−3.29 (2H, m), 3.12 (H, dd), 3.03(H, dd), 2.30 (3H, s), 1.73 (H, d), 1.28 (H, d).

[0486]¹³C-NMR (CDCl₃/DMSO): 144.70, 143.30, 134.58, 129.44, 128.40,126.77, 120.58, 113.34, 59.60, 56.73, 56.44, 51.81, 36.09, 21.00

[0487] 2-(4-Chlorophenyl)-2,5-diazabicyclo[2.2.1]heptane (133)

[0488]¹H-NMR (CDCl₃): 7.14 (2H, d), 6.45 (2H, d), 4.23 (H, s), 3.76 (H,s), 3.62 (H, d), 3.08 (H, d), 3.00 (H, d), 2.89 (H, d), 1.92 (H, d),1.81 (H, d), 1.56 (H, b).

[0489]¹³C-NMR (CDCl₃): 145.53, 128.78, 120.56, 113.44, 59.77, 56.83,56.19, 49.50, 37.26

[0490] 5-(4-fluorophenyl)-2-p-tosyl-2,5-diazabicyclo[2.2.1]heptane (134)

[0491]¹H-NMR (CDCl₃): 7.68 (2H, d), 7.27 (2H, d), 6.82-6.95 (2H, m),6.40−6.29 (2H, m), 4.49 (H, s), 4.23 (H, s), 3.52 (H, d), 3.46 (H, dd),3.25 (H, dd), 3.13 (H, d) 2.41 (3H, s), 1.86 (H, d), 1.41 (H, d).

[0492]¹³C-NMR (CDCl₃): 157.63, 152.96, 143.56, 142.80, 142.77, 135.21,129.65, 127.17, 115.73, 115.29, 113.20, 113.05, 59.97, 57.35, 56.93,51.79, 36.60, 21.34.

[0493] 5-(4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane (135)

[0494]¹H-NMR (CDCl₃): 7.05−6.83 (2H, m), 6.52−6.28 (2H, m ), 4.20 (H,s), 3.76 (H, s), 3.64 (H, dd), 3.10 (H, d), 3.00 (H, dd), 2.88 (H, d),1.96 (H, d), 1.81 (H, d), 1.76 (H, b).

[0495]¹³C-NMR (CDCl₃): 157.27, 152.63, 143.61, 115.67, 115.32, 113.13,112.98, 60.21, 57.04, 56.27, 49.21, 37.29.

[0496] 5(3-Chloropropyl)-2-phenyl-2,5-diazabicyclo[2.2.1]heptane (136):

[0497] 129 (1.0 g, 5.7 mmoles), 0.23 g (5.7 mmoles) of sodium amide and20 mL of toluene are refluxed for 1 hour. After that, 0.93 g (5.7mmoles) of 1-bromo-3-chloropropane in 10 mL of toluene are addeddropwise over a period of 20 minutes and refluxed for 2 hours. Aftercooling, the reaction mixture is extracted with 2N HCl (2−50 mL) and theaqueous phase made alkaline with 30% sodium hydroxide and extracted withtoluene (3−40 mL). Evaporation and bulb tube evaporation (boiling pointat 0.05 mbar: 120°-130° C.) resulted in 0.97 g (70.4% of the theoreticalyield) of 136 as a colorless oil.

[0498] TLC: chloroform: MeOH=9:1

[0499]¹H-NMR (CDCl₃): 7.19 (2H, m), 6.69 (3H, m), 4.27 (H, b), 3.68 (H,b), 3.60 (H, dd), 3.18−2.89 (5H, m), 2.36−1.36 (7H, m).

[0500]5-(2-Chloroethyl)-2-(4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane(137):

[0501] 135 (1.0 g, 5.2 mmoles), 0.21 g (5.3 mmoles) of sodium amide and20 mL of toluene are refluxed for 1 hour. After that, 0.77 g (5.2mmoles) of 1-bromo-3-chloroethane in 10 mL of toluene are added dropwiseover a period of 20 minutes and refluxed for 2 hours. After cooling, thereaction mixture is extracted with 2N HCl (2×50 mL) and the aqueousphase made alkaline with 30% sodium hydroxide and extracted with toluene(3−40 mL). Evaporation and bulb tube evaporation (boiling point at 0.05mbar: 100°-120° C.) resulted in 0.76 g (56.7% of the theoretical yield)of 137 as a colorless oil.

[0502] TLC: chloroform: MeOH=9:1

[0503]¹H-NMR (CDCl₃): ¹H-NMR (CDCl₃): 7.05−6.83 (2H, m), 6.52−6.28 (2H,m), 4.20 (H, s), 3.76 (H, s), 3.64 (H, dd), 3.10 (H, d), 3.00 (H, dd),2.88 (H, d), 2.66−2.28 (2H, m), 2.20−1.90 (2H, m) 1.96 (H, d), 1.81 (H,d), 1.76 (H, b).

[0504] 2-t-Boc-5-(2-hydroxyethyl)-2,5-diazabicyclo[2.2.1]heptane (138):

[0505] Gaseous ethylene oxide is introduced slowly for 1.5 hours at 20°C. and with stirring into a solution of 2.5 g of2-t-Boc-2,5-diazabicyclo[2.2.1]heptane in 50 mL of methanol, thetemperature increasing to 35° C. The solution was evaporated and theoily crude product distilled using a bulb tube (boiling point 0.05 mbar,90°-100° C.); 1.60 g of 138 as a colorless oil (52.5% of the theoreticalyield).

[0506]¹H-NMR (CDCl₃): 4.31 (H, d), 3.54 (2H, t), 3.40 (H, d), 3.18 (H,dd), 2.92 (H, dd), 2.73 (2H, m), 2.56 (H, d), 1.84 (H, d), 1.72 (H, d),1.54 (9H, s)

[0507]¹³C-NMR (CDCl₃): 157.80, 79.21, 61.76, 61.24, 59.82, 59.68, 56.40,56.09, 55.73, 55.43, 49.95, 49.21, 36.01, 35.36, 28.27

[0508] 2-Benzyl-5-(2-hydroxyethyl)-2,5-diazabicyclo[2.2.1]heptane (139):

[0509] Procedure: See 138

[0510] Yield: 83.3% of the theoretical yield of 139, as a colorless oilwith a boiling point of 120°-130° C. at 0.005 mbar.

[0511]¹H-NMR (CDCl₃): 7.30 (5H, m), 3.67-3.74 (2H, d), 3.55 (2H, m),3.30 (2H, b), 3.20 (H, b), 2.87 (H, dd), 2.75 (H, dd), 2.71 (H, t), 2.67(2H, m), 1.78 (H, m), 1.68 (H, m).

[0512]¹³C-NMR (CDCl₃): 139.63, 128.29, 128.09, 126.65, 62.49, 61.16,59.80, 58.19, 56.45, 56.26, 56.19, 33.64

[0513] 2-Benzyl-5-cyanomethyl-2,5-diazabicyclo[2.2.1]heptane (140)

[0514] Finely ground potassium carbonate, as well as 1.3 mL of freshlydistilled chloroacetonitrile were added to a solution of 3 g of2-benzyl-2,5-diazabicyclo[2.2.1]heptane in 40 mL of anhydrous tolueneand refluxed for 10 hours with vigorous stirring. The solution wascooled, filtered and evaporated. Bulb tube distillation (boiling point:110°-120° C. at 0.01 mbar) resulted in 3.57 g of 140 as a colorless oil(97% of the theoretical yield).

[0515]¹H-NMR (CDCl₃): 7.41−7.18 (5H, m), 3.65, 3.75 (2R d), 3.53, 3.46(2H, d), 3.45 (H, b), 3.37 (H, b), 3.04 (H, d), 2.73 (H, d), 2.71(H,dd), 2.68 (H, d), 1.82 (H, d), 1.77 (H, d).

[0516]¹³C-NMR (CDCl₃): 139.41, 128.08, 127.92, 126.51, 117.03, 62.47,61.39, 57.97, 57.09, 55.97, 41.23, 33.00.

[0517] 2-Benzyl-5-(2-aminoethyl)-2,5-diazabicyclo[2.2.1]heptane (141)

[0518] A solution of 5.74 g (25.3 mmoles) of 140 and 50 mL of NH₃ werehydrogenated with 2 g of Raney nickel in a steel autoclave at 100 bar H₂and 100° C. for 2 hours. The catalyst was filtered off with suction andthe solution was evaporated and distilled using a bulb tube (boilingpoint: 135°-145° C. at 0.01 mbar): 5.02 g of 141 as a colorless oil (87%of the theoretical yield).

[0519]¹H-NMR (CDCl₃): 7.18 (5H, m), 3.70 (2H, d), 3.23 (2H, b),2.69−2.42 (8H, m), 1.71 (H, ddd), 1.65 (H, ddd), 1.70 (2H, b).

[0520]¹³C-NMR (CDCl₃): 139.62, 127.92, 127.65, 126.19, 62.15, 61.15,57.92, 57.30, 56.19, 55.91, 40.80, 33.32

[0521] 2-Benzyl-5-cyanoethyl-2,5-diazabicyclo[2.2.1]heptane (142)

[0522] Freshly distilled acrylonitrile (2.5 g) is added to a solution of3 g of 2-benzyl-2,5-diazabicyclo[2.2.1]heptane in 40 mL of anhydroustoluene and refluxed with vigorous stirring. The solution was cooled,filtered and evaporated. Bulb tube distillation (boiling point:120°-130° C. at 0.01 mbar) resulted in 3.43 g of 142 as a colorless oil(88% of the theoretical yield).

[0523]¹H-NMR (CDCl₃): 7.39−7.17 (5H, m), 3.70 (2H, d), 3.30 (H, b), 3.26(H, b), 2.88−2.59 (4H, m), 2.74 (H, d) 2.63 (H, dd), 2.42 (2H, t), 1.75(H, dd), 1.64 (H, dd).

[0524]¹³C-NMR (CDCl₃): 139.50, 128.17, 127.99, 126.57, 118.64, 62.40,61.15, 58.68, 56.59, 55.91, 49.77, 33.66, 18.21

[0525] 2-Benzyl-5-(2-aminopropyl)-2,5-diazabicyclo[2.2.1]heptane (143)Analog: Similar to 141

[0526] Yield: 83.7% of the theoretical, colorless oil, boiling point:120°-130° C. at 0.01 mbar

[0527]¹H-NMR (CDCl₃): 7.18 (5H, m), 3.70 (2H, d), 3.31 (H, b), 3.16 (H,b), 2.91−2.48 (8H, m), 2.22 (2H, b), 1.71 (2H, m), 162 (H, d), 1.49 (H,d)

[0528]¹³C-NMR (CDCl₃): 139.46, 127.76, 127.54, 126.03, 61.55, 60.90,57.76, 56.08, 55.32, 51.58, 39.99, 33.05, 31.97

[0529] Ethyl 2-(5-benzyl-2,5-diazabicyclo[2.2.1]heptane)-acetate (144)

[0530] Ethyl bromoacetate (2.5 g) and 3 g of dried, finely groundpotassium carbonate are added to a solution of 3 g of2-benzyl-2,5-diazabicyclo[2.2.1]heptane in 40 mL of toluene and refluxedfor 8 hours with vigorous stirring. The solution was cooled, filteredand concentrated. Bulb tube distillation (boiling point: 125°-130° C. at0.01 mbar) resulted in 1.79 g of 144 as a colorless oil (40% of thetheoretical yield).

[0531]¹³C-NMR (CDCl₃): 170.96, 139.44, 128.14, 128.03, 126.62, 62.31,61.64, 60.36, 58.06, 56.90, 55.47, 55.33, 33.74, 14.03

[0532] 2-tBoc-5-diphenylmethyl-2,5-diazabicyclo[2.2.1]heptane (145)

[0533] Triethylamine (0.8 g) and 1.55 g of diphenylmethyl chloride areadded to a solution of 1.5 g of 2-tBoc-2,5-diazabicyclo[2.2.1]heptane inanhydrous THF and refluxed with stirring for 4 hours. The THF was thenevaporated off, taken up in 50 mL of saturated sodium hydrogen carbonatesolution and extracted 3 times with 30 mL of ether. Evaporation resultedin 2.2 g of yellowish crystals of 145 (78% of the theoretical yield).

[0534]¹H-NMR (CDCl₃): 7.43−7.11 (10H, m), 4.81 (H, b), 4.31 (H, d), 3.40(H, d), 3.18 (H, dd), 2.92 (H, dd), 2.56 (H, d), 1.84 (H, d), 1.72 (H,d), 1.54 (9H, s)

[0535] Literature List

[0536] (1) S. Y. Han, J. E. Sweeney, E. S. Bachman, E. J. Schweiger, J.T. Coyle, B. M. Davis, M. M. Joullie, Eur. J. Med. Chem. 27, 673-687(1992)

[0537] (2) T. Kametani, K. Yamaki, S. Yaki, K. Fukumoto, J. Chem. Soc.(C), 2602 (1969)

[0538] (3) T. Kametani, K. Shishido, E. Hayashi, J. Org. Chem., 36, 1259(1971)

[0539] (4) T. Kametani, C. Seino, K. Yamaki, S. Shibuya, K. Fukumoto, J.Chem. Soc., 1043-1047 (1971)

[0540] (5) T. Kametani, K. Yamaki, T. Terui, S. Shibuya, K. Fukumoto, J.Chem. Soc. Perkin I, 1513-1516 (1972)

[0541] (6) T. Kametani, K. Yamaki, T. Terui, J. Het. Chem. 10, 35-37(1973)

[0542] (7) J. Szewczyk, A. Lewin, F. I. Caroll, J. Het. Chem 25,1809-1811 (1988)

[0543] (8) R. Vlahov, D. Krikorian, G. Spassov, M. Chinova, I. Vlahov,G. Parushev, G. Snatzke, L. Ernst, K. Kieslich, W. Abraham, W. Shedrick,Tetrahedron 45, 3329 (1989)

[0544] (9) P. Strehlke, G. A. Hoyer, E. Schröder, E. Arch. Pharm. 388(2), 94-109 (1975)

[0545] (10) M. Ishizaki, K. Ozaki, A. Kanematsu, T. Isoda, O. Hoshino,J. Org. Chem. 58, 3877-3885 (1993)

[0546] (11) C. Nogueiras, W. Döpke, G. Lehmann, tetrahedron Letters35,3249-3250 (1971)

[0547] (12) H. H. Wassermann, R. J. Gambale, Tertrahedron 48 (35),7059-7070 (1992)

[0548] (13) J. M. Pons, A. Pommier, J. Lerpiniere, P. Kocienski, J.Chem. Soc., Perkin Trans I 14, 1549-1551 (1993)

[0549] (14) T. Kioshi, Yakugaku Zhassi, 104, 1009 (1984)

[0550] (15) B. M. Davsis, Pat WO 88/08708 A1 (1988)

[0551] (16) Stichting Biomed. Res., Pat NL 88000350 A1 (1989)

[0552] (17) J. Bastida; F. Viladomat; J. M. Llabres, S. Quiroga, C.Codina, M. Rubiralta, Planta Med. 56, 123, 1990

[0553] (18) S. J. Han, S. C. Mayer, E. J. Schweiger, B. M. Davis, M. M.Joullie, Boorg. Med. Chem. Lett. 1, 579, 1991

[0554] (19) D. Albrigt, N. Goldman, Pat. 64219 (1968)

[0555] (20) H. G. Boit, W. Döpke, A. W. Beitner, Chem. Ber. 90, 2197(1957)

[0556] (21) R. Matusch, M. Kreh, U. Müller, Helv. Chim. Acta 77, 1611(1994)

[0557] (22) H. M. Fales, L. D. Gioffrida, W. C. Wildman, J.Am. Chem.Soc. 78, 4145 (1956)

[0558] (23) S. Kobayashi, K. Satoh, S. Numata.; T. Hingu, M. Kihara,Phytochemistry 30, 675 (1991)

[0559] (24) R. W. Kosley, L. Davis, V. Taberna, Pat. EP 653427 A1(1995), U.S. Pat. No. 93-137,440

[0560] (25) R. W. Kosley, L. Davis, V. Taberna, Pat. EP 649346 A1(1995), U.S. Pat. No. 93-137,444

[0561] (26) R. W. Kosley, L. Davis, V. Taberna, Pat. EP 648771 A1(1995), U.S. Pat. No. 93-137,443

[0562] (27) W. S. K. Kaisha, EP 393400 (1990), JP 82321 (1989), JP238064 (1989)

[0563] (28) D. L. Romero e.y., Pat WO 91-09849 (1991), U.S. Pat. No.90-07390 (1990)

[0564] (29) J. E. Arrowsmith, Pat. EP 324543 (1989), GB 8800694 (1988)

[0565] (30) D. G. Hutchinson, Pat. WO 9323384 (1993), U.S. Pat. No.92-880,432 (1992)

[0566] (31) P. S. Portoghese, A. A. Mikhail, J. Org. Chem. 31, 1059(1966)

[0567] (32) T. F. Braish, D. E. Fox, J. Org. Chem., 55, 1684-1687 (1990)

[0568] (33) S. Ziklova, K. Ninov, Tr. Nauchniozsled. Khim. Farm. Inst.12, 35-46 (1982)

[0569] (34) K. Fujii, K. Tomino, H. Watanabe, J. Pharm. Soc. Japan 74,1049-51 (1954)

[0570] (35) H. G. Morren, R. Danayer, R. Linz, J. Mathieu, H. Strubbe,S. Trolin, Ind. Chim. Belge 22, 409-416 (1957)

[0571] (36) D. C. Jones, M. A. Winter, K. S. Hirsch, N. Stamm, H. M.Taylor, J. Med. Chem. 33 (1), 416-429 (1990)

[0572] (37) G. L. Regnier, C. G. Guillonneau, J. L. Duhault, F. P.Tisserand, G. Saint-Romas, S. M. Holstorp, Eur. J. Med. Chem 22, 243-250(1987)

[0573] (38) G. E. Martin e.a., J. Med. Chem. 32, 1056 (1989)

[0574] (39) Z. Budai, Hpat. HU 61737 (1991)

[0575] (40) D. W. Smith, Pat. EP 345808 (1988), U.S. Pat. No. 204,845(1988), U.S. Pat. No 338,253 (1989)

[0576] (41) J. P. Yevich, EP 400661 (1990), U.S. Pat. No. 360,657(1989), U.S. Pat. No. 503,197 (1990)

[0577] (42) T. F. Braish, Pat. EP 397351 (1990), U.S. Pat. No. 350,423(1989), U.S. Pat. No. 423,063 (1989)

[0578] (43) am 15. Oktober 1995 bekanntgemachte österr. Patentanmeldung1980/94 vom 21. Oktober 1994

[0579] (44) G. L. Ellman K. D. Courtney, V. Andres, R. M. Featherstone,Biochem. Pharmacol 7, 88(1961). Sanochemia Ltd. 1996.04.19 vertretendurch:

1. Compounds of the general formula (II)

in which R₁, R₂ either are the same or different and represent hydrogen,F, Cl, Br, I, CN, NC, OH, SH, NO₂, SO₃H, NH₂, CF₃, or substituted orunsubstituted straight or branched lower (C₁-C₆) alkyl or alkoxy or anamino group substituted by one or more substituted or unsubstitutedstraight or branched lower (C₁-C₆) alkyl or alkyl carbonyl or alkoxycarbonyl group or a COOH, COO alkyl, CONH, CON alkyl group or—(CH₂)_(n)—Cl, —(CH₂)_(n)—Br, —(CH₂)_(n)—OH, —(CH₂)_(n)—COOH,—(CH₂)_(n)—CN, —(CH₂)_(n)—NC, in which R₁-R₂ may together form—CH═CH—CH═CH—, —O—(CH₂)_(n)—O—, with n=1 to 3; R₃ is OCH₃ or the same asR₁, or R₂—R₃ can jointly form: —O—(CH₂)_(n)—O—, with N=1 to 3; R₄, R₅:are both hydrogen or, alternatively, any combination of hydrogen or analkyl, alkenyl, alkinyl, or S—R₈, wherein R₈ is hydrogen or asubstituted or unsubstituted straight or branched lower (C₁-C₁₀) alkylgroup SO—R₈, SO₂R₈ OH, O-protective group O—CS—N—R₈ (thiourethanes)O—CO—N—R₉, wherein R₉ has the following meaning:

O—CO—R₈, including esters with a substitution pattern of amino acids asfollows

R₄, R₅ may jointly be hydrazone (═N—NH—R₁₀, ═N—N (R₁₀, R₁₁), oximes(═N—O—R₁₁), wherein R₁₀ is hydrogen, a substituted or unsubstitutedstraight or branched lower (C₁-C₆) alkyl or alkyl carbonyl or alkylcarbonyloxy group as well as a sulfonic acid group, and R₁₁ is hydrogen,a substituted or unsubstituted straight or branched lower (C₁-C₆) alkylor alkyl carbonyl group, as well as a sulfonic acid group; R₄ and R₅ mayalso be:

wherein Y₁, Y₂═O, S, NH or N—R₁₀ (excess valences in each case are —H)wherein, in the event that R₄ is not H, R₅ can also be OH and, in theevent that R₅ is not H, R₄ can also be OH. G₁, G₂: jointly or separatelyhave the meaning: —C(R₁₃, R₁₄)—, wherein R₁₃, R₁₄ can be hydrogen, OH, asubstituted or unsubstituted straight or branched lower alkyl, aryl,alkoxy or aryloxy group or jointly an alkyl spiro group (C₃ to C₇ spiroring). G₁ and G₂ may jointly represent

with m=1 to 7 G₃: represents CH₂ or ═CO R₆ represents a group-(G₄)_(p)-(G₅)_(q)-G₆ with p, q=0-1, in which G₄ satisfies the followingdefinition —(CH₂)_(s)—, —C(R₁₅, R₁₆)—(CH₂)_(s)—, with R=1 to 6 and R₁₅,R₁₆=hydrogen, or substituted or unsubstituted straight or branched loweralkyl, cycloalkyl, or aryl groups —O— or —NR₁₅

wherein s=1-4, and t=0-4

that is an ortho, meta or para disubstituted aromatic

wherein G₇=NR₁₅, O or S, G₅ can be identical with or different from G₄and, in the event that P=1, additionally represents —S—, G₆ fulfills thefollowing definition:

wherein R₁₇, R₁₈, R₁₉ and R₂₀ individually or jointly are the same ordifferent, and are hydrogen, substituted or unsubstituted straight orbranched lower alkyl, cycloalkyl or aryl groups, where R₁₇ and R₁₈ andR₁₉ and R₂₀ can jointly form a cycloalkyl group (with a ring size of3-8) G₈=O, S, NH, NR₂₁—(CH₂)_(n)—, R₂₁═CHO, COOR₁₇ or a heteroarylgroup, which is unsubstituted or substituted identically or differentlyby one or several F, Cl, Br, I, NO₂, OH, alkyl, alkyloxy, CN, NC or CF₃,CHO, COOH, COOalkyl, SO₃H, SH or S-alkyl groups, or a methyl group,which is substituted by 1-3 phenyl groups, which are unsubstituted orsubstituted identically or differently by one or more F, Cl, Br, I, NO₂alkyl, alkyloxy, CN, NC or CF₃ groups, wherein G₈ can also be:

a substituted or unsubstituted straight or branched lower alkyl,alkenyl, alkinyl, cycloalkyl or aryl groups, —O—R₁₇, —NR₁₇R₁₈phthalamido, —CN or —NC; R₇ is identical with R₆ or represents —O—⁽⁻⁾(N-oxide) or a free electron pair (e-pair), wherein R₆ and R₇ can alsoform a common ring, 3 to 8 carbon atoms in size and X exists only if,and represents an ion of a pharmacologically unstable inorganic ororganic acid, where R₅ and R₆ are present and the nitrogen atom thuscarries a positive charge; and Z=N or N⁺ in the event that R₄ and R₇ arepresent jointly and R₇ is not O⁻.—
 2. Compounds having the generalformula (III):

wherein R₂₂ is a (hetero) aryl group, which is unsubstituted orsubstituted identically or differently by one or several F, Cl, Br, I,NO₂, NH₂, OH, alkyl, alkoxy, CN, NC or CF₃, COOH, COOalkyl, SO₃H, SH orS-alkyl groups or a methyl group, which is substituted by two phenylgroups, which are substituted identically or differently by one or moreF, Cl, Br, I, NO₂, NH₂, OH, alkyl, alkoxy, CN, NC or CF₃, CHO, COOH,COOalkyl, SO₃H, SH or S-alkyl groups, R₁₇, R₁₈, n, s having the meaningsgiven for the general formula (I) and R₂₃=-(G₅)_(q)-(G₄)_(p)-G₉ whereinG₄ and G₅ have the meanings given for the general formula (I) and G₉ isdefined as F, Cl, Br, I, OH, O-ts, O-ms, O-triflate, COOH COCl CHO,—O—R₁₇, —NR₁₇R₁₈, phthalimido, —CN or —NC or by other groups suitablefor nucleophilic substitutions, addition reactions, condensationreactions, etc.
 3. A compound of claim 2 having the formula:


4. A compound of claim 2 having the formula:


5. A composition consisting essentially of a compound according to claim2, in admixture with a pharmaceutically acceptable excipient.
 6. Amethod for the treatment of Alzheimer's disease, comprisingadministering to a human patient in need thereof a pharmaceuticallyacceptable amount of a compound as claimed in claim
 2. 7. A method forthe treatment of trisomy 21, comprising administering to a human patientin need thereof a pharmaceutically acceptable amount of a compound asclaimed in claim 2.